Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same

ABSTRACT

The present invention relates to pharmaceutical compositions and kits comprising pharmaceutical compositions, and methods for administering pharmaceutical compositions comprising active contraceptive drugs in a patient. Specifically, the pharmaceutical compositions may comprise progestogen-only contraceptives (“POC”), such as Drospirenone.

This application claims priority under 35 U.S.C. § 119 to U.S.Provisional Patent Application 61/368,396, filed Jul. 28, 2010.

FIELD OF THE INVENTION

The present invention relates to the field of contraceptive kits,pharmaceutical compositions and methods of administering and uses forthe kits and pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Several contraceptives which comprise synthetic progestogens and nooestrogen are commercially available. These contraceptives called“progestogen-only contraceptives” encompass implants, uterine deliverysystems and pills.

Progestogen only contraceptives (“POC”) have the advantage of avoidingthe combined administration of estrogens as compared to traditionalcontraceptive combined pills. POCs, however, display several majordrawbacks. Because of their low contraceptive reliability, POCs have tobe taken each day at the same time without a pill-free or placebointerval.

The bleeding patterns for women who take POCs may be also be altereddeeply as compared to the natural menstrual cycle, since amenorrhea orunscheduled bleeding or spotting may occur. Accordingly, POCs are poorlyused and are usually indicated for women who cannot tolerate estrogen,for women in post-partum period and for women who are breast-feeding(Amy, Tripathi, 2009, BMJ, 339, 563-568; Mandisk, 2008, OBSTETRICMEDICINE, 1,78-87).

Drospirenone (CAS: 67392-87-4;6b,7b:15b,16b-Dimethylen-3-oxo-17a-pregn-4-ene-21,17-carbolactone) is asynthetic progestogen with a pharmacological profile very closelyrelated to that of natural progesterone. Drospirenone (“DRSP”) is devoidof androgenic, glucocorticoid and antiglucocorticoid activity but doespossess potent antimineralocorticoid and antiandrogenic properties. Itwas shown that oral daily doses of at least 3 mg of drospirenone areable to inhibit ovulation over a single treatment cycle of 21 days. Thecombination of 3 mg drospirenone/30 μg ethinylestradiol provides areasonable contraceptive safety margin by inhibiting ovulation with alow frequency of follicular maturation (Rosenbaum et al., 2000, THEEUROPEAN JOURNAL OF CONTRACEPTION AND REPRODUCTIVE HEALTH CARE, 5,16-24).

Drospirenone (DRSP) is thus an appropriate progestin ingredient whichmay avoid the side-effects occurring with conventional syntheticprogestogens such as weight gain and breast tension when combined withan estrogen for use as a contraceptive. DRSP is also likely to minimizefluid retention and to have neutral effects on metabolic and vascularrisks (Blode et al., 2000, THE EUROPEAN JOURNAL OF CONTRACEPTION ANDREPRODUCTIVE HEALTH CARE, 5, 256-264; Sitruk-Ware, 2006, HUMANREPRODUCTION UPDATE, 12, 169-178). It has been also reported thatdrospirenone may treat moderate acne because of its well-establishedanti-androgenic properties.

Drospirenone as a contraceptive ingredient is available only in oralcombined pills such as those marketed under the name of Yasmin® (3 mgDRSP/30 μg ethinylestradiol), Yaz® (3 mg DRSP/20 μg ethinylestradiol)and Yasminelle® (3 mg DRSP/20 μg ethinylestradiol). These pills compriseethinylestradiol which acts to increase the ovulation inhibitory effectof drospirenone and to ensure contraception and cycle stability. Thepatent application WO2008031631 describes combined oral contraceptivesin which drospirenone is used as a progestative agent andethinylestradiol is replaced by the phytoestrogen 8-prenylnaringenin.These contraceptives may be included in modified release formulations of8-prenylnaringenin and drospirenone which may continuously distributethe active ingredients for the gastro-intestinal transit time ofgenerally 12 h-16 h.

The commercially available contraceptives Yasmin®, Yaz® and Yasminelle®comprise drospirenone in a micronized form which promotes its rapiddissolution in vitro and ensures its good oral bioavailability. It isalso the case for Angeliq® which is a hormone replacement medicamentcombining drospirenone and estradiol. However, such formulations arecharacterized by a high plasma concentration peak for drospirenone afteroral intake. High plasma concentrations are not preferred in patientstreated with drospirenone because of a correlation between high C_(max)and certain undesirable side effects as well as poor general tolerancewhen hormonal levels fluctuate too much each and every day.

Accordingly, there is still a need in the art for novel contraceptivekits and for novel pharmaceutical compositions comprising drospirenone.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions and kitscomprising pharmaceutical compositions, and methods for administeringpharmaceutical compositions for preventing pregnancy in a patient. Thepharmaceutical compositions may comprise active drugs such as activecontraceptive drugs. Specifically, the active drugs may compriseprogestogen-only contraceptives (“POC”) for inhibiting ovulation. Inspecific embodiments, the pharmaceutical compositions and kits andmethods of administering the pharmaceutical compositions allow for noveldosing regimens of POCs and provide pharmacokinetic profiles thatreflect these novel dosing regimens.

In one embodiment, the pharmaceutical composition of the presentinvention may comprise an active contraceptive drug, wherein thepharmaceutical composition allows for a 28 day daily dosing regimen, andwherein after initial administration of the active contraceptive drughas established its contraceptive effect in a patient, the patient mayskip up to 4 doses within any 28 day daily dosing regimen period. In aspecific embodiment, the skipped up to 4 doses may be on non-consecutivedays. In another specific embodiment, the skipped up to 4 doses may beon consecutive days. In another embodiment of the present invention, thepharmaceutical composition may further allow during the 28 day dailydosing regimen for the patient to skip up to two non-consecutive days ofthe active contraceptive drug, provided the active contraceptive drugskipped dose is taken within about 24 hrs after the up to two skippednon-consecutive days. In another embodiment, the active contraceptivedrug may inhibit ovulation. In another embodiment, the contraceptiveeffect may comprise inhibiting ovulation.

In another specific embodiment, the active contraceptive drug may be aprogestogen-only contraceptive (POC). In another specific embodiment,the POCs may be selected from one or more of the group consisting ofdrospirenone, I7-hydroxy progesterone esters, 19-nor-17-hydroxyprogesterone esters, 17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione and dienogest. In a specificembodiment, the POC may be drospirenone. In another specific embodiment,each daily dose of drospirenone may comprise a dosage amount of at leastabout 2 mg.

In another specific embodiment, the pharmaceutical compositions may alsohave a particular pharmacokinetic profile. In one embodiment, thepresent invention may be a pharmaceutical composition wherein each dailydose of the active contraceptive drug, when orally administered to apatient in fasting conditions, provides a pharmacokinetic profile forthe active contraceptive drug having:

-   -   i) a T_(max) ranging from about 2.2 hrs to 6 hrs; and    -   ii) a mean C_(max) which is less than about 30 ng/ml.

In a specific embodiment, the pharmacokinetic profile for the activecontraceptive drug may additionally comprise an AUC_(0h-tlast) which isat least 300 ng·h/ml. In another specific embodiment, the AUC_(0h-tlast)may be at least 350 ng·h/ml. In another specific embodiment, the themean C_(max) may range from about 15 ng/ml to about 30 ng/ml. In anotherspecific embodiment, the active contraceptive drug with the abovepharmacokinetic parameters may be a POC. In another specific embodiment,the POC may be drospirenone. In another embodiment, drospirenone may bethe only administered active contraceptive drug.

In another specific embodiment, a kit may comprise the pharmaceuticalcompositions described above. In a specific embodiment, the kit maycomprise one or more packaging units wherein each packaging unitcomprises up to 28 daily active dosage units comprising an activecontraceptive drug in a pharmaceutical composition, wherein thepharmaceutical composition allows for a 28 day daily dosing regimen, andwherein after initial administration of the active drug has establishedits contraceptive effect in a patient, the patient may skip up to 4doses within any 28 day daily dosing regimen period. In a specificembodiment, the skipped up to 4 doses may be on non-consecutive days. Inanother specific embodiment, the skipped up to 4 doses may be onconsecutive days. In another embodiment of the present invention, thekits may provide pharmaceutical compositions that further allow duringthe 28 day daily dosing regimen for the patient to skip up to twonon-consecutive days of the active contraceptive drug, provided theactive contraceptive drug skipped dose is taken within about 24 hrsafter the up to two skipped non-consecutive days. In another embodiment,the active contraceptive drug may inhibit ovulation. In anotherembodiment, the contraceptive effect may comprise inhibiting ovulation.

The present invention also includes methods of administering thepharmaceutical compositions described above. In one embodiment, themethods of the present invention may comprise administering acomposition comprising an active contraceptive drug, wherein thepharmaceutical composition allows for a 28 day daily dosing regimen, andwherein after initial administration of the active contraceptive drughas established its contraceptive effect in a patient, the patient mayskip up to 4 doses within any 28 day daily dosing regimen period. In aspecific embodiment, the skipped up to 4 doses may be on non-consecutivedays. In another specific embodiment, the skipped up to 4 doses may beon consecutive days. In another embodiment of the present invention, themethods may comprise administering pharmaceutical compositions whichfurther allows during the 28 day daily dosing regimen for the patient toskip up to two non-consecutive days of the active contraceptive drug,provided the active contraceptive drug skipped dose is taken withinabout 24 hrs after the up to two skipped non-consecutive days. Inanother specific embodiment, the kits may comprise pharmaceuticalcompositions comprising an active contraceptive drug with theabove-described pharmacokinetic paramaters. In another specificembodiment, the active contraceptive drug may be a progestogen-onlycontraceptive (POC). In another specific embodiment, the POC may bedrospirenone. In another embodiment, drospirenone may be the onlyadministered active contraceptive drug.

In another embodiment of the present invention, the patient may have ahigher risk for developing a complication from the administration of anestrogen than the general population. In a specific embodiment, thecomplication from the administration of an estrogen may be due to thepatient having one or more conditions or characteristics selected fromthe group consisting of a higher risk for developing thromboembolismthan the general population, acquired or genetic thrombophilia orhypercoagulability, an age of 35 years or over who smoke cigarettes, ahigher risk for stroke than the general population, sickle-cell diseaseor sickle-cell anemia, a higher risk than the general population formyocardial infarction, and women currently lactating.

In another embodiment of the present invention, the patient may be awoman and have one or more conditions or characteristics selected fromthe group consisting of being predisposed to hyperkalemia, sufferingfrom kidney, liver or adrenal diseases, and being on daily, long-termtreatment for a chronic condition with medications predisposed tohyperkalemia. In a specific embodiment, the medications predisposed tohyperkalemia may be selected from one or more of the group consisting ofa non steroidal anti-inflammatory, potassium-sparing diuretics,potassium supplementation medication, angiotensin-converting enzyme(ACE) inhibitors, angiotensin-II receptor antagonists and heparin. Inanother specific embodiment, the patient may be in need to improvetolerance for s drospirenone. In another specific embodiment, thepatient may be preparing for Hormone Replacement Therapy medicaments.

In another embodiment, the methods of the present invention may compriseproducing a pharmacokinetic profile of an active drug in a patient,wherein the pharmacokinetic profile comprises a mean T_(max) rangingfrom about 2.2 hrs to about 6 hrs, and a mean C_(max) which is less thanabout 30 ng/ml, wherein the pharmacokinetic profile is measured in saidpatient after orally administering a single daily dosage unit of saidactive drug to said patient in fasting conditions. In another specificembodiment, the pharmacokinetic profile may additionally comprise anAUC_(0h-tlast) which is at least about 300 ng·h/ml. In another specificembodiment, the AUC_(0h-tlast) may be at least about 350 ng·h/ml. Inanother specific embodiment, the active drug may be an activecontraceptive drug. In another embodiment, the active contraceptive drugmay inhibit ovulation. In another specific embodiment, the activecontraceptive drug may be a POC. In another specific embodiment, the POCmay be selected from one or more of the group consisting ofdrospirenone, 17-hydroxy progesterone esters, 19-nor-17-hydroxyprogesterone esters, 17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione and dienogest. In anotherspecific embodiment, the POC may be drospirenone. In another specificembodiment, drospirenone may be the only administered active drug thatinhibits ovulation.

In another embodiment of the present invention, the methods may includeadministering to a patient the compositions provided above. In anotherembodiment, the patient may be a woman and have one or more conditionsor characteristics selected from the group consisting of beingpredisposed to hyperkalemia, suffering from kidney, liver or adrenaldiseases, and being on daily, long-term treatment for a chroniccondition with medications predisposed to hyperkalemia. In a specificembodiment, the medications predisposed to hyperkalemia may be selectedfrom one or more of the group consisting of a non steroidalanti-inflammatory, potassium-sparing diuretics, potassiumsupplementation medication, angiotensin-converting enzyme (ACE)inhibitors, angiotensin-Il receptor antagonists and heparin. In anotherspecific embodiment, the patient may be in need to improve tolerance fors drospirenone. In another specific embodiment, the patient may bepreparing for Hormone Replacement Therapy medicaments.

In another embodiment of the present invention, the pharmaceuticalcompositions may include active drugs that produce certainpharmacokinetic profiles. In a specific embodiment, the pharmaceuticalcomposition may comprise an active drug, wherein a single daily dosageunit of the composition, when orally administered to a patient infasting conditions provides a pharmacokinetic profile for the activedrug having:

-   -   i) a T_(max) ranging from about 2.2 hrs to 6 hrs; and    -   ii) a mean C_(max) which is less than about 30 ng/m.

In another specific embodiment, the pharmacokinetic profile may alsoinclude an AUC_(0h-tlast) which is at least 300 ng·h/ml. In anotherspecific embodiment, the AUC_(0h-tlast) may be at least 350 ng·h/ml. Inanother specific embodiment, the active drug may be an activecontraceptive drug. In another embodiment, the active contraceptive drugmay inhibit ovulation. In another specific embodiment, the activecontraceptive drug may be a POC. In another embodiment, the POC may beselected from one or more of the group consisting of drospirenone,17-hydroxy progesterone esters, 19-nor-17-hydroxy progesterone esters,17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione and dienogest. In anotherembodiment, the POC may be drospirenone. In another specific embodimentof the present invention, each daily dosage unit may comprise a dosageamount of at least about 2 mg.

In another embodiment, the patient may be a woman and have one or moreconditions or characteristics selected from the group consisting ofbeing predisposed to hyperkalemia, suffering from kidney, liver oradrenal diseases, and being on daily, long-term treatment for a chroniccondition with medications predisposed to hyperkalemia. In a specificembodiment, the medications predisposed to hyperkalemia may be selectedfrom one or more of the group consisting of a non steroidalanti-inflammatory, potassium-sparing diuretics, potassiumsupplementation medication, angiotensin-converting enzyme (ACE)inhibitors, angiotensin-II receptor antagonists and heparin. In anotherspecific embodiment, the patient may be in need to improve tolerance fors drospirenone. In another specific embodiment, the patient may bepreparing for Hormone Replacement Therapy medicaments.

In another embodiment of the present invention, the pharmaceuticalcompositions may comprise active drugs characterized by dissolutiontests. In a specific embodiment, a pharmaceutical composition maycomprise an active drug, wherein:

-   -   (a) a daily active oral dosage unit of the composition comprises        an amount of said active drug of at least 2 mg, and    -   (b) the daily active oral dosage unit comprises the active drug        in a form such that when subjected to an in vitro dissolution        test according to the USP XXIII Paddle Method,        -   (i) no more than 50% of the active drug initially present in            the the daily active dosage unit is dissolved within 30            minutes, and        -   (ii) at least 50% of the active drug is dissolved in a time            range from 3 hours to 4 hours.

In another specific embodiment, the active drug may be an activecontraceptive drug. In another embodiment, the active contraceptive drugmay inhibit ovulation. In another specific embodiment, the activecontraceptive drug may be a POC. In another embodiment, the POC may beselected from one or more of the group consisting of drospirenone,17-hydroxy progesterone esters, 19-nor-17-hydroxy progesterone esters,17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione and dienogest. In anotherembodiment, the POC may be drospirenone. In another embodiment, eachdaily dosage unit of drospirenone may comprise a dosage amount of atleast about 2.0 mg to about 6.0 mg. In a specific embodiment, the eachdaily dosage unit of drospirenone may comprise a dosage amount of atleast about 3.0 mg to about 4.5 mg.

The present invention may also include kits that comprise one or morepackaging units wherein each packaging unit comprises dosage units withan active drug that provides certain pharmacokinetic parameters. In aspecific embodiment, the kit may comprise one or more packaging unitswherein each packaging unit comprises 21 to 28 daily active dosage unitscomprising an active drug and wherein a single active dosage unit, whenorally administered under fasting conditions, is adapted to provide apharmacokinetic profile for the active drug consisting of one or more ofthe pharmacokinetic parameters selected from the group consisting of:

-   -   i) a T_(max) ranging from about 2.2 hrs to 6 hrs; and    -   ii) a mean C_(max) which is less than about 30 ng/ml.

In another specific embodiment, the pharmacokinetic profile may alsocomprise an AUC_(0h-tlast) which is at least 300 ng·h/ml. In anotherspecific embodiment, the AUC_(0h-tlast) may be at least 350 ng·h/ml. Inanother embodiment, the mean C_(max) may range from about 15 ng/ml toabout 30 ng/ml. In another specific embodiment, the active drug may bean active contraceptive drug. In another embodiment, the activecontraceptive drug may inhibit ovulation. In another specificembodiment, the active contraceptive drug may be a POC In anotherembodiment, the POC may be selected from one or more of the groupconsisting of drospirenone, 17-hydroxy progesterone esters,19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosterone andderivatives thereof, 17α-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, norgestrel,d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime, cyproteroneacetate, gestodene, desogestrel, etonorgestrel, norgestimate,norelgestromin, chlormadione and dienogest. In another embodiment, thePOC may be drospirenone.

In another embodiment, the patient may be a woman and have one or moreconditions or characteristics selected from the group consisting ofbeing predisposed to hyperkalemia, suffering from kidney, liver oradrenal diseases, and being on daily, long-term treatment for a chroniccondition with medications predisposed to hyperkalemia. In a specificembodiment, the medications predisposed to hyperkalemia may be selectedfrom one or more of the group consisting of a non steroidalanti-inflammatory, potassium-sparing diuretics, potassiumsupplementation medication, angiotensin-converting enzyme (ACE)inhibitors, angiotensin-II receptor antagonists and heparin. In anotherspecific embodiment, the patient may be in need to improve tolerance fors drospirenone. In another specific embodiment, the patient may bepreparing for Hormone Replacement Therapy medicaments. In anotherspecific embodiment, each daily dosage unit of drospirenone may comprisea dosage amount of at least about 2 mg. In another specific embodiment,the amount of drospirenone in each daily active unit dosage may rangefrom about 2.0 mg to about 6.0 mg. In another specific embodiment, theamount of drospirenone in each daily active unit dosage may range fromabout 3.0 mg to about 4.5 mg.

The kits of the present invention may also include contraceptive kitscomprising one or more packaging units that comprise dissolution testsof an active drug, such as drospirenone. In a specific embodiment, thecontraceptive kit may comprise one or more packaging units wherein eachpackaging unit comprises 21 to 28 daily active dosage units and wherein

-   -   (a) the amount of drospirenone in each daily active dosage unit        is at least 2 mg without estrogen, and    -   (b) each daily active dosage unit comprises drospirenone in a        form such that when subjected to an in vitro dissolution test        according to the USP XXIII Paddle Method,        -   (i) no more than 50% of the drospirenone initially present            in the said daily active dosage unit is dissolved within 30            minutes and (ii) at least 50% of the said drospirenone is            dissolved in a time range from 3 hours to 4 hours.

In a specific embodiment, drospirenone may be the sole contraceptiveingredient. In another specific embodiment, the amount of drospirenonein each daily active unit dosage may range from about 2.0 mg to about6.0 mg. In another specific embodiment, the amount of drospirenone ineach daily active unit dosage may range from about 3.0 mg to about 4.5mg.

One embodiment of the present invention may include pharmaceuticalcompositions comprising progestogen-only contraceptive (POC) defined bya d50 particle size. In a specific embodiment, the POC may have a d50particle size which ranges from about 10 μm to about 60 μm. In aspecific embodiment, the d50 particle size may range from about 10 μm toabout 30 μm. In another specific embodiment, the surface area of theparticles may be from about 2000 cm²/g to about 8500 cm²/g. In anotherspecific embodiment, the surface area of the particles may be from oneor more selected from the group consisting of about 2000 cm²/g, about2500 cm²/g, about 3000 cm²/g, about 3500 cm²/g, about 4000 cm²/g, about4500 cm²/g, about 5000 cm²/g, about 5500 cm²/g, about 6000 cm²/g, about6100 cm²/g, about 6200 cm²/g, about 6300 cm²/g, about 6400 cm²/g, about6500 cm²/g, about 6600 cm²/g, about 6700 cm²/g, about 6800 cm²/g, about6900 cm²/g, about 7000 cm²/g, about 7500 cm²/g, about 8000 cm²/g andabout 8500 cm²/g.

In another embodiment, the POC may be selected from one or more of thegroup consisting of drospirenone, 17-hydroxy progesterone esters,19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosterone andderivatives thereof, 17α-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, norgestrel,d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime, cyproteroneacetate, gestodene, desogestrel, etonorgestrel, norgestimate,norelgestromin, chlormadione and dienogest. In another embodiment, thePOC may be drospirenone. In another embodiment, the particles may havethe pharmacokinetic profiles as characterized above.

One embodiment of the present invention may also include methodscomprising sizing drospirenone to a particular d50 particle size. In aspecific embodiment, the methods may comprise sizing drospirenone to ad50 particle size which ranges from about 10 μm to about 60 μm bysubjecting drospirenone to one or mills selected from the groupconsisting of a ball mill, a hammer mill, a fluid energy mill, a rodmill, a cutting mill and an oscillating granulator. In a specificembodiment, the methods may further comprise the step of subjectingdrospirenone to a vibrating sieve. In another embodiment, the methodsmay comprise sizing drospirenone to a d50 particle size which rangesfrom about 10 μm to about 60 μm by:

-   -   (i) dissolving drospirenone in a water-miscible solvent; and    -   (ii) dispersing the resulting solution in cold water under        stirring so that to induce the precipitation of drospirenone.

In another specific embodiment, the methods may further comprise thestep of subjecting drospirenone to a vibrating sieve. In a specificembodiment of the present invention, the water-miscible solvent may beselected from one or more of the group consisting of methanol, ethanol,isopropanol, dimethylformamide, tetrahydrofuran, dioxane or dimethylsulfoxide, dimethylacetamide and acetone. In another specificembodiment, the water-miscible solvent may be dimethylacetamide.

In another embodiment of the present invention, the pharmaceuticalcompositions may comprise a progestogen-only contraceptive (POC),wherein the pharmaceutical composition allows for a 28 day daily dosingregimen, and wherein after initial administration of POC has inhibitedovulation in a patient, the patient may skip up to 4 doses within any 28day daily dosing regimen period. In another embodiment, thepharmaceutical composition may further allow during the 28 day dailydosing regimen for the patient to skip up to two non-consecutive days ofthe POC, provided the POC skipped dose is taken within about 24 hrsafter the up to two skipped non-consecutive days. In a specificembodiment, the skipped up to 4 doses may be on non-consecutive days. Inanother specific embodiment, the skipped up to 4 doses may be onconsecutive days. In another embodiment, the POC may inhibit ovulation.

In another embodiment of the present invention, the pharmaceuticalcompositions may comprise drospirenone, wherein the pharmaceuticalcomposition allows for a 28 day daily dosing regimen, and wherein afterinitial administration of drospirenone has inhibited ovulation in apatient, the patient may skip up to 4 doses within any 28 day dailydosing regimen period. In another embodiment, the pharmaceuticalcomposition may further allow during the 28 day daily dosing regimen forthe patient to skip up to two non-consecutive days of the drospirenone,provided the drospirenone skipped dose is taken within about 24 hrsafter the up to two skipped non-consecutive days. In a specificembodiment, the skipped up to 4 doses may be on non-consecutive days. Inanother specific embodiment, the skipped up to 4 doses may be onconsecutive days. In another embodiment, the drospirenone may inhibitovulation.

In another embodiment of the present invention, the methods of thepresent invention may include administering compositions that comprise aprogestogen-only contraceptive (POC), wherein the pharmaceuticalcomposition allows for a 28 day daily dosing regimen, and wherein afterinitial administration of POC has inhibited ovulation in a patient, thepatient may skip up to 4 doses within any 28 day daily dosing regimenperiod. In another embodiment, the pharmaceutical composition mayfurther allow during the 28 day daily dosing regimen for the patient toskip up to two non-consecutive days of the POC, provided the POC skippeddose is taken within about 24 hrs after the up to two skippednon-consecutive days. In a specific embodiment, the skipped up to 4doses may be on non-consecutive days. In another specific embodiment,the skipped up to 4 doses may be on consecutive days. In anotherembodiment, the POC may inhibit ovulation.

In another embodiment of the present invention, the methods of thepresent invention may include administering compositions that comprisedrospirenone, wherein the pharmaceutical composition allows for a 28 daydaily dosing regimen, and wherein after initial administration ofdrospirenone has inhibited ovulation in a patient, the patient may skipup to 4 doses within any 28 day daily dosing regimen period. In anotherembodiment, the pharmaceutical composition may further allow during the28 day daily dosing regimen for the patient to skip up to twonon-consecutive days of the drospirenone, provided the drospirenoneskipped dose is taken within about 24 hrs after the up to two skippednon-consecutive days. In a specific embodiment, the skipped up to 4doses may be on non-consecutive days. In another specific embodiment,the skipped up to 4 doses may be on consecutive days. In anotherembodiment, the drospirenone may inhibit ovulation.

In another embodiment of the present invention, the kits may compriseone or more packaging units wherein each packaging unit comprises up to28 daily active dosage units comprising a progestogen-only contraceptive(POC) in a pharmaceutical composition, wherein the pharmaceuticalcomposition allows for a 28 day daily dosing regimen, and wherein afterinitial administration of POC has inhibited ovulation in a patient, thepatient may skip up to 4 doses within any 28 day daily dosing regimenperiod. In another embodiment, the pharmaceutical composition mayfurther allow during the 28 day daily dosing regimen for the patient toskip up to two non-consecutive days of the POC, provided the POC skippeddose is taken within about 24 hrs after the up to two skippednon-consecutive days. In a specific embodiment, the skipped up to 4doses may be on non-consecutive days. In another specific embodiment,the skipped up to 4 doses may be on consecutive days. In anotherembodiment, the POC may inhibit ovulation.

In another embodiment of the present invention, the kits may compriseone or more packaging units wherein each packaging unit comprises up to28 daily active dosage units comprising drospirenone in a pharmaceuticalcomposition, wherein the pharmaceutical composition allows for a 28 daydaily dosing regimen, and wherein after initial administration ofdrospirenone has inhibited ovulation in a patient, the patient may skipup to 4 doses within any 28 day daily dosing regimen period. In anotherembodiment, the pharmaceutical composition may further allow during the28 day daily dosing regimen for the patient to skip up to twonon-consecutive days of the drospirenone, provided the drospirenoneskipped dose is taken within about 24 hrs after the up to two skippednon-consecutive days. In a specific embodiment, the skipped up to 4doses may be on non-consecutive days. In another specific embodiment,the skipped up to 4 doses may be on consecutive days. In anotherembodiment, the drospirenone may inhibit ovulation.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Particle size distribution

FIG. 1 shows the cumulative distribution curve (cdf, filled diamonds)and the probability density function curve (pdf, filled squares) fordrospirenone (DRSP) batch 080053. The distribution experimental datawere obtained by laser diffraction method. X-coordinate: particle size(μm) in log scale. Left Y-coordinate: cumulative distribution inpercentage. Right Y-coordinate: probability density function.

FIG. 2: In vitro dissolution profiles

FIG. 2 shows the in vitro dissolution profiles for tablet (A-3 mg)obtained from DRSP batch 080053 as described in Example 1 (inventive,curve n° 2) and comparative tablets, namely Yasminelle® (curve n° 4),tablets CO1-3 mg (curve n° 3) and tablets CO2-3 mg (curve n° 1). Eachtablet comprises 3 mg of DRSP. The in vitro dissolution profiles weredetermined by the USP XXIII Paddle Method as described in Example 2.X-coordinate: time in hours, Y-coordinate: mean dissolution percentageof DRSP relating to the initial amount of DRSP contained in the testedtablet.

FIG. 3a and FIG. 3b : Mean drospirenone serum concentration versus timecurves

FIG. 3a shows DRSP plasma mean concentration versus time curves obtainedafter the oral administration of a single tablet of reference product,i.e. Yasminelle® (empty squares) or after the oral administration of asingle tablet obtained from DRSP batch 080053 as described in Example 1(test product, filled squares). In both cases, the DRSP dosage was 3 mg.These clinical data were obtained during a monocentric, open,randomized, single-dose, two period crossover clinical trial conductedon 14 healthy female volunteers as described in Example 3 part 1. Eachvolunteer received randomly, an oral single dose of 1 tablet of the testproduct or one tablet of Yasminelle® on two single occasions, alwaysunder fasting conditions. Study periods were separated by a realwash-out phase of 7 days. In each study, blood samples were collectedbefore the administration of the tablet (pre-dose, time 0) and at 0:30,1:00, 1:30, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 24:00, 48:00 and72:00 hours post dosing for assaying the DRSP plasma concentration., TheX-coordinate: time after the oral administration of the tablet (inhours); and Y-coordinate: mean plasma concentration of DRSP in ng/ml(arithmetic mean).

FIG. 3b shows DRSP plasma mean concentration versus time curves obtainedafter the oral administration of a single tablet of reference producti.e. Yasminelle® (empty squares) or after the oral administration of asingle tablet CO1-3 mg (filled diamonds) or after the oraladministration of a single tablet CO2-3 mg (filled squares) underfasting conditions (see Example 3, part 2). The X-coordinate: time afterthe oral administration of the tablet (in hours); the Y-coordinate: meanplasma concentration of DRSP in ng/ml (arithmetic mean).

FIGS. 4 a, 4 b and 4 c: Simulation based on pharmacokinetic results fromclinical trial described in Example 3

FIG. 4a and FIG. 4b show the experimental DRSP plasma mean concentrationversus time curves: (i) for the oral administration of a single tabletof Yasminelle® (comparative, filled squares); and (ii) for the oraladministration of a single tablet as described in Example 1 (A-3 mg,invention, empty triangles). Both Yasminelle® tablet and tablet A-3 mgcontains 3 mg of DRSP. FIGS. 4a and 4b also show the predicted mean DRSPplasma concentration versus time curve (invention, empty diamonds)obtained for the oral administration of a tablet similar to thatdescribed in Example I, but containing 4 mg of DRSP (tablet A-4mg). Sucha curve was extrapolated from the experimental pharmacokinetic dataobtained in the clinical trial described in Example 3, part 1. TheX-coordinate: time after the oral administration of the tablet (inhours); the Y-coordinate: mean plasma concentration of DRSP in ng/ml.

FIG. 4c shows the mean plasma DRSP concentration versus time curvesresulting from the repeated administration of one tablet of Yasminelle®(curve n° 1), that of one tablet A-3 mg (curve n° 3), and that of onetablet A-4 mg (curve n° 2), every 24 hours. These curves were obtainedby extrapolation of experimental pharmacokinetic data obtained in theclinical trial described in Example 3. The X-coordinate: time after theoral administration of the first tablet (in hours); the Y-coordinate:mean plasma concentration of DRSP in ng/ml.

FIG. 5a and FIG. 5 b: In vitro dissolution profile and mean drospirenoneserum concentration versus time curve for tablet comprising 4 mg of DRSP(B-4 mg).

FIG. 5a shows the mean in vitro dissolution profile for tablets obtainedfrom DRSP batch N° PR 100003 as described in Example 5 (see part 1). Thetablet comprises 4 mg of DRSP. The X-coordinate: time in hours; theY-coordinate: mean dissolution percentage of DRSP relating to theinitial amount of DRSP contained in the tested tablet.

FIG. 5b shows DRSP plasma mean concentration versus time curves obtainedafter the oral administration of a single tablet of reference product,i.e. Yasminelle® (empty squares) or after the oral administration of asingle tablet B-4 mg (tilled squares) under fasting conditions (seeExample 5, part 2). The X-coordinate: time after the oral administrationof the tablet (in hours); the Y-coordinate: mean plasma concentration ofDRSP in ng/ml.

FIGS. 6a and 6 b: Individual plasma levels of progesterone and estradiolin patients during treatment period and follow up period.

FIGS. 6a and 6b show the results of a clinical trial aiming toillustrate the contraceptive efficiency of the contraceptivecompositions according to the invention. The methodology of the clinicaltrial is described in Example 4. Briefly, the treatment period comprisestwo treatment cycles in which the subjects took one pill of 4 mg DRSP(tablet B-4 mg) from day 1 to day 24 and one placebo tablet from day 25to day 28 of each treatment cycle at a fixed hour. On day 5 and day 13of the second cycle, the pill intake was delayed for 24 hours (i.e. nopill was taken on day 5 and day 13 and that 2 pills were taken on day 6and day 14, respectively). The complete study consisted of a 56-daytreatment period and a 28-day post-treatment follow-up period. The pillcorresponds to tablet B-4 mg.

FIG. 6a shows the variation of the individual plasma levels ofprogesterone during the treatment period and the follow-up period. TheX-coordinate: time in days after the first pill intake; theY-coordinate: progesterone level in ng/ml.

FIG. 6b shows the variation of the individual plasma levels of estradiolduring the treatment period and the follow-up period. The X-coordinate:time in days after the first pill intake; The Y-coordinate: estradiollevel in pg/ml.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical compositions andcontraceptive kits comprising a plurality of active daily dosage units.Each active daily dosage unit may include a pharmaceutical compositioncomprising an active drug. In a specific embodiment, each daily dosageunit may include a pharmaceutical composition comprising an active drugsuch as a progestogen-only contraceptive (POC). In another specificembodiment, each daily dosage unit may include a pharmaceuticalcomposition comprising drospirenone. In preferred embodiments, the saidpharmaceutical composition may include drospirenone, without estrogen.In other words, the contraceptive kit comprises a progestogen-onlycontraceptive kit. Drospirenone may be the sole contraceptive agentpresent within the pharmaceutical composition. The active daily dosageunit enables to prevent pregnancy when daily administered to a woman ofchild-bearing age over a period of 21 to 28 consecutive days. The numberof active daily dosage units in the contraceptive kit may vary dependingon the contraceptive method in which the contraceptive kit is intendedto be used.

In order to disclose the contraceptive kit of the invention in a mannersufficiently clear and complete, the pharmaceutical composition of theactive daily dosage units of the kit and the contraceptive method forwhich the kit is dedicated are fully-described in Sections 1 and 2,respectively, hereunder. In Section 3, specific embodiments of thecontraceptive kit of the invention are also described.

1. Pharmaceutical Compositions

The commercially available drospirenone-containing contraceptive pillscomprise both ethinyl-estradiol and micronized drospirenone. Accordingto European patent EP1214076B1, the micronized form of drospirenonepromotes its rapid dissolution in vitro. This rapid dissolution in vitrois claimed to be a necessary condition for obtaining a goodbioavailability via the oral route. The rapid dissolution rate ofdrospirenone in vitro is assessed to be correlated to a rapid absorptionin vivo of DRSP which avoids its degradation by gastric or intestineenvironments. Several other patents and patent applications, such asWO2006128907, or WO2009138224, describe drospirenone compositions whichexhibit a rapid dissolution of drospirenone in vitro.

Accordingly, the international application WO2006128907 shows thatsurfactants may enhance the dissolution rate of non-micronizeddrospirenone having a specific surface area lower than 10 000 cm²/g. Theinternational application WO2009138224 provides that the dissolutionrate of drospirenone may be significantly improved by co-millingdrospirenone with an appropriate carrier so as to obtain drospirenone inan amorphous state.

As mentioned in EP1214076B1, a rapid dissolution of drospirenone invitro generally means that at least 70% of the drospirenone is dissolvedwithin 30 minutes when the composition is subjected to an in vitrodissolution assay such as USP XXIII Paddle Method II.

Surprisingly, in view of these data, the present invention showed,through in vivo pharmacokinetic assays, that a rapid dissolution ofdrospirenone in vitro is not required for obtaining a good oralbioavailability. In this respect, the present invention provides adrospirenone-containing composition with a slow dissolution rate ofdrospirenone in vitro and which exhibits a similar mean AUC value (AreaUnder the Curve) as compared to Yasminelle® when orally administered tofemale patients.

Moreover, the present invention relates to DRSP-containing compositionswhich also display a significantly mean reduced C_(max) value (MaximumPlasma Concentration) associated with a delayed mean t_(max) value fordrospirenone as compared to Yasminelle®. The decrease of DRSP C_(max)improves the tolerance of the DRSP-containing composition by reducing oravoiding side-effects, in particular those related to the plasma levelof potassium.

Drospirenone has an anti-mineralocorticoid property which leads to anincrease of potassium excretion and also, to an increase of potassiumplasma level. It has been suggested that the C_(max) of drospirenonecorrelates to the C_(max) of potassium released after drospirenoneadministration. Such an increase of potassium plasma concentration afterdrospirenone administration may lead to hyperkalemia which is known toinduce various disorders such as dizziness, palpitations, muscleweakness and even cardiac arrhythmia.

When orally administered, the DRSP-containing compositions according tothe invention, induces a reduced plasmatic C_(max) for drospirenone. Areduced C_(max) for DRSP is expected to reduce the release of potassiumin plasma. Consequently, in the case of the compositions according tothe invention, the tolerance for drospirenone may be improved especiallyfor women who are predisposed to hyperkalemia, to women who suffer fromkidney, liver or adrenal diseases, and for women who are on daily,long-term treatment for a chronic condition with medications predisposedto hyperkalemia. Medications predisposed to hyperkalemia include,without being limited to, non steroidal anti-inflammatory drugs,potassium-sparing diuretics, potassium supplementation,angiotensin-converting enzyme (ACE) inhibitors, angiotensin-Il receptorantagonists and heparin.

Consequently, the DRSP-containing compositions according to theinvention may be particularly appropriate to prepare any oral medicamentin which the mean C_(max) value for DRSP should be controlled in orderto improve the tolerance for drospirenone. For example, the compositionsaccording to the invention may be used for preparing Hormone ReplacementTherapy medicaments (HRT).

Since the DRSP-containing composition of the invention combined areduced C_(max) with a delayed t_(max) and an AUC_(0h-tlast) sufficientto provide a contraceptive effect, the said compositions are appropriatefor use in progestogen-only pills. As illustrated in Example 5, part 3,the compositions according to the present invention provide an efficientand stable contraceptive drospirenone blood level when dailyadministered to a female patient. Thus, the co-administration of anoestrogen to ensure contraception and cycle stability is not required.Since the mean C_(max) value is significantly reduced, the contraceptivecompositions of the invention provides a more stable plasmaconcentration of drospirenone, i.e. a DRSP plasma concentration with lowfluctuations between two consecutive administrations. Such a featurefurther reduces the incidence of unscheduled spotting and bleeding and,thus, significantly improves the bleeding profile as compared toconventional POCs.

As described in Example 5, the compositions of the present inventionremains a contraceptive even when a placebo period is introduced in thecontraceptive regimen and some daily pills are missed. Accordingly, thecompositions will exhibit a higher contraceptive reliability than otherprogestogen only pills, which will allow the patients to be lesscompliant with treatment without risking unwanted pregnancy.

Also the contraceptive compositions of the invention—which do notcontain estrogen—will be as efficient as a combined oral pill withoutinducing the side effects related to estrogen, in particular, withoutincreasing the risk of cardiovascular events. Thus, in some embodimentsof the invention, the pharmaceutical compositions may be appropriate tobe used as an oral contraceptive. In some other specific embodiments,the pharmaceutical composition of the invention may be used as aprogestogen-only pill.

As used herein “progestogen-only contraceptive”, or “progestogen-onlypill” means a pill or a contraceptive which comprises progestogens assole contraceptive agents and does not comprise any estrogen.

By “composition having an improved pharmacokinetic profile fordrospirenone” as used herein, is thus meant that the oral administrationof a single daily dosage unit of said drospirenone-containingcomposition provides a pharmacokinetic profile for drospirenonecharacterized by a delayed mean t_(max) and a reduced mean C_(max) ascompared to the administration of a single daily dosage unit ofYasminelle®. The pharmacokinetic profile of Yasminelle® is described inExample 3

In some embodiments, the invention may provide a pharmaceuticalDRSP-containing composition that when orally administered as a singledaily dosage unit of said composition, is adapted to provide apharmacokinetic profile for DRSP having a mean C_(max) which is lessthan 85% of the mean C_(max) obtained after the oral administration of asingle dosage unit of Yasminelle®. The pharmaceutical DSRP-containingcomposition according to the present invention may further becharacterized by, when orally administered, a single daily dosage unitof the composition is adapted to provide a pharmacokinetic profile forDRSP having a mean t_(max) which is at least 150% of the mean t_(max)obtained after the oral administration of a single dosage unit ofYasminelle®

Thus, the administration of a single dosage unit of the composition mayprovide a mean AUC_(0h-tlast) which is sufficient to produce thepharmaceutical or the biological effect which is sought by theadministration of drospirenone. In the present invention, thepharmaceutical or biological effect generally refers to a contraceptiveeffect.

When the compositions of the invention are used as a contraceptive, itmay be further required that the mean AUC_(0h-tlast) obtained upon theadministration of a single daily dosage unit of said composition is atleast 70% of the mean AUC_(0h-tlast) obtained in the case ofYasminelle®. In other words, in some embodiments of the invention, thedaily dosage unit of the pharmaceutical composition according to theinvention may posses a combination of physical and/or chemical featuressuch that, when orally administered, the daily dosage unit is adapted toprovide a pharmacokinetic profile having the following characteristics:

-   -   (i) a mean C_(max) which is no more than 85% of the mean C_(max)        obtained after the oral administration of a single dosage unit        of Yasminelle® and    -   (ii) a mean t_(max) which is at least 150% of the mean t_(max)        obtained after the oral administration of a single dosage unit        of Yasminelle®, and, optionally, a mean AUC_(0h-tlast) which is        at least 70% of the mean AUC_(0h-tlast) obtained after the oral        administration of a single dosage unit of Yasminelle®.

In some embodiments, the mean AUC_(0h-tlast) may be at least 85% of themean AUC_(0h-tlast) obtained after the oral administration of a singledosage unit of Yasminelle®. In some embodiments, the pharmaceuticalcompositions of the invention display one or more of the previousmentioned pharmacokinetic characteristics. The AUC_(0h-tlast), theC_(max) and the t_(max) are determined based on the drospirenone plasmaconcentration versus time curve. According to the present invention, fora given drospirenone-containing composition, the drospirenone plasmaconcentration versus time curve may be determined by following plasmadrospirenone concentration over a period of about 72 h after a singleoral intake of one daily dosage unit of the said drospirenone-containingcomposition.

The single oral administration of the said drospirenone-containingcomposition, in one embodiment, may be preferably performed in fastingconditions i.e. without food and not close to mealtime (in general,approximately 6 h-10 h after meal) since food ingestion may modify theabsorption rate of drospirenone in the gastrointestinal tractus.

The t_(max) and C_(max) values refer to the maximum DRSP plasmaconcentration and the time to reach it, respectively, after the oraladministration of a single daily dosage unit of the DRSP-containingcomposition of interest. In other words, t_(max) and C_(max) refer tothe characteristics of drospirenone plasma concentration peak observedafter the oral intake of a single daily dosage unit of the compositionof interest.

The AUC_(0h-tlast) corresponds to the area obtained by integration ofthe drospirenone plasma concentration versus time over the interval[0h-tlast], the point “0h” referring to the oral intake of a singledaily dosage unit of the composition of interest and the point“t_(last)” refers to the last time for which plasma concentration ofDRSP can be quantifiable.

DRSP plasma concentration may be determined by well-known methods. Forexample, an appropriate method of quantification comprises theextraction of DRSP from human plasma and then its quantification usingliquid chromatography coupled with tandem mass spectrometry.

In a preferred embodiment, one skilled in the art may adapt theanalytical method described by Kirk a al (Rapid Communication in MassSpectrometry, 2006; 20:1247-1252). Such a method comprises a step ofderivatization of drospirenone with Girard P hydrazine solution in orderto increase the response of DRSP during the subsequent MS analysis. Thismethod is generally appropriate to quantify DRSP in human EDTA plasmaover a concentration range from about 0.25 to about 100 ng/ml.

As used herein, the mean AUC_(0h-tlast), the mean C_(max) and the meant_(max) refer to arithmetic mean values determined from individualpharmacokinetic data obtained for a group of healthy female volunteersof child-age bearing subjected to a single oral administration of onedaily dosage unit of a drospirenone-containing composition. The group ofhealthy female volunteers may comprise enough women to providestatistically confident pharmacokinetic results. Preferably, the saidgroup comprises at least ten healthy women of child-bearing age.

As used herein, a healthy woman of child-bearing age refers to apre-menopause Caucasian female between 18 and 40 years, with normal bodyweight and with no health problem, in particular, with no metabolism,renal, liver or gynaecologic disorders. A “normal body weight” refers toa body mass index (BMI) ranging from 18 to 29 kg/m².

Preferably, such volunteers have not taken any hormone-containingcompositions within 3 months prior to the trial to determine thepharmacokinetic parameters of interest.

The mean C_(max), t_(max) and AUC_(0h-tlast) for Yasminelle® and for thedrospirenone-containing composition according to the invention aredetermined for the same group of female patients. Between theadministration of the single daily dosage unit of Yasminelle® and thatof the DRSP-containing composition according to the invention, thefemale volunteers may be subjected to a washout period of at least 7days. The mean C_(max), the mean t_(max) and the mean AUC_(0h-tlast) forDRSP may be determined from raw individual pharmacokinetic data bywell-known statistical methods of the prior art.

For example, all endpoints listed above may be determined in amodel-independent way. The highest concentration really measured and thetime at which it was registered after each dose in any given volunteermay be regarded as C_(max) and t_(max) respectively according to thealgorithm of the program NC_PKP.sas.

The daily dosage unit of the DRSP containing-composition of theinvention may comprise at least 2 mg of drospirenone. A daily amount ofDRSP from 3 mg to 4.5 mg may be preferred when the composition of theinvention is used as contraceptive.

As used herein, Yasminelle® is a combined oral pill commercialized byBayer/Schering. The daily dosage unit of Yasminelle® is a coated tabletwhich comprises 3 mg of micronized drospirenone and ethinylestradiolbetadex clathrate in an amount corresponding to 20 μg ofethinylestradiol. The tablet further comprises lactose monohydrate,maize starch and magnesium stearate as main excipients. The coating ofthe tablet comprises hypromellose, talc, titane oxide and iron oxidered.

As used herein, Yasminelle® (marketed under the name of Jasminelle® inFrance) refers to the pharmaceutical product covered by the FrenchMarketing Authorization related to CIS number (Code d'Identification deSpécialité) 65052799 and revised on Sep. 17, 2009.

In a preferred embodiment, the pharmacokinetic parameters (namelyC_(max), t_(max) and AUC_(0h-tlast)) are determined after the first oraladministration of a single unit dosage of the DRSP-containingcomposition of interest, said first oral administration occurring infasting conditions.

In a more general aspect, the present invention may provide apharmaceutical composition comprising an active drug, when orallyadministered as a single daily dosage unit of said composition, isadapted to provide a pharmacokinetic profile for said active drug havinga mean C_(max) which is less than about 30 ng/ml. The pharmaceuticalcomposition comprising an active drug may be further characterized inthat, when orally administered, a single daily dosage unit of saidcomposition is adapted to provide a pharmacokinetic profile for saidactive drug having a mean t_(max) which is at least about 2.2 h.

In another embodiment, the mean AUC_(0h-tlast) obtained upon theadministration of a single daily dosage unit of said composition may beat least about 300 ng*ml/h. The daily dosage unit of the pharmaceuticalcomposition according to the invention may possesses a combination ofphysical and/or chemical features such that, when orally administered,the daily dosage unit is adapted to provide a pharmacokinetic profilehaving the following characteristics:

-   -   (i) a mean C_(max) which is less than about 30 ng/ml    -   (ii) a mean t_(max) of at least about 2.2 h; and, optionally,    -   (iii) a mean AUC_(0h-tlast) of at least about 300 ng*h/ml.

MOM In another specific embodiment, the T_(max) may range from about 2.2hrs to 6 hrs. In another specific embodiment, said AUC_(0h-tlast) may beat least 350 ng·h/ml.

In another embodiment of the present invention, the active drug, whenorally administered and provides such a pharmacokinetic profile, may bea drug that inhibits ovulation. In a specific embodiment, the activedrug may be a progestogen-only contraceptive (POC). In another specificembodiment, the POC may be selected from one or more of the groupconsisting of drospirenone, 17-hydroxy progesterone esters,19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosterone andderivatives thereof, 17α-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, norgestrel,d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime, cyproteroneacetate, gestodene, desogestrel, etonorgestrel, norgestimate,norelgestromin, chlormadione and dienogest. In a specific embodiment,the POC may be drospirenone.

In a specific embodiment, the present invention may provide apharmaceutical DRSP-containing composition, when orally administered asa single daily dosage unit of said composition, is adapted to provide apharmacokinetic profile for DRSP having a mean C_(max) which is lessthan about 30 ng/ml. The said pharmaceutical DRSP-containingcompositions may be further characterized in that, when orallyadministered, a single daily dosage unit of said composition is adaptedto provide a pharmacokinetic profile for DRSP having a mean t_(max)which is at least about 2.2 h.

The administration of a single dosage unit of the said compositionincluding DRSP may provide a mean AUC_(0h-tlast) which is sufficient toproduce the pharmaceutical or the biological effect which is sought bythe administration of drospirenone. Accordingly, when the compositionsof the invention are used as a contraceptive, it may be further requiredthat the mean AUC_(0h-tlast) obtained upon the administration of asingle daily dosage unit of said composition is at least about 300ng*ml/h. In other words, in some embodiments, the daily dosage unit ofthe pharmaceutical composition according to the invention may possess acombination of physical and/or chemical features such that, when orallyadministered, the daily dosage unit is adapted to provide apharmacokinetic profile having the following characteristics:

-   -   (i) a mean C_(max) which is less than about 30 ng/ml    -   (ii) a mean t_(max) of at least about 2.2 h        and, optionally, a mean AUC_(0h-tlast) of at least about 300        ng*h/ml.

In some embodiments, the pharmaceutical composition of the invention maydisplay all the previous mentioned pharmacokinetic characteristics.

As used herein, the term “about” before a “specific value” defines arange from “the specific value minus at least 10% of the specific value”to “the specific value plus at least 10% of the specific value”. Forexample, “about 50” defines a range from 45 or less to 55 or more. Inaddition, it may define a range where “the specific value minus at least20% of the specific value” to “the specific value plus at least 20% ofthe specific value” Further, it may define a range where “the specificvalue minus at least 30% of the specific value” to “the specific valueplus at least 30% of the specific value” and so on.

A mean AUC_(0h-tlast) of at least about 300 ng*h/mL includes a meanAUC_(0h-tlast) of at least about 310 ng*h/mL, at least about 320ng*h/mL, at least about 330 ng*h/mL, at least about 340 ng*h/mL, atleast about 350 ng*h/mL, at least about 360 ng*h/mL, at least about 370ng*h/mL, at least about 380 ng*h/mL, at least about 390 ng*h/mL, atleast about 400 ng*h/mL, at least about 410 ng*h/mL at least about 420ng*h/mL, at least about 430 ng*h/mL. In some embodiments, the meanAUC_(0h-tlast) is at least about 350 ng*h/ml.

A mean t_(max) of at least about 2.2 h includes a mean t_(max) of atleast about 2.5 h, of at least about 3.0 h, of at least about 3.5 h, ofat least about 4 h. In a specific embodiment, the mean t_(max) does notexceed 6 hours in order to not significantly impair the bioavailabilityof DRSP. Thus, the mean t_(max) preferably may range from about 2.2 h toabout 6 h. In some embodiments, a t_(max) ranges from about 3.0 h toabout 4.0 h.

A mean C_(max) which is less than about 30 ng/ml includes a C_(max) lessthan about 28 ng/ml, less than about 26 ng/ml, less than about 24 ng/ml,less than about 22 ng/ml, less than about 20 ng/ml, less than about 19ng/ml, less than about 18 ng/ml, less than about 17 ng/ml, less thanabout 16 ng/ml, less than about 15 ng/ml, less than about 14 ng/ml. Insome embodiments, the mean C_(max) ranges from about 15 ng/ml to about30 ng/ml. In other embodiments, the mean C_(max) ranges from about 15ng/ml to about 26 ng/ml.

In certain embodiments, the daily dosage unit of the pharmaceuticalcomposition according to the invention may be adapted to provide apharmacokinetic profile having the following characteristics:

-   -   (i) a mean C_(max) ranges from 15 ng/ml to 30 ng/ml,    -   (ii) a mean t_(max) ranges from 2.2 h to 6 h, and    -   (iii) optionally, a mean AUC_(0h-tlast) of at least about 300        ng*h/ml,        when the said daily dosage unit is administered under fasting        condition.

In a specific embodiment, the pharmacokinetic parameters (namelyC_(max), t_(max) and AUC_(0h-tlast)) may be determined after the firstoral administration of a single unit dosage of the active drug, saidfirst oral administration occurring in fasting conditions.

In one embodiment, pharmaceutical compositions may comprise an activedrug, wherein a single daily dosage unit of the composition, when orallyadministered to a patient in fasting conditions provides apharmacokinetic profile for the active drug having:

-   -   i) a T_(max) ranging from about 2.2 hrs to 6 hrs; and    -   ii) a mean C_(max) which is less than about 30 ng/ml;

In some embodiments, the oral administration of the active drug providesa pharmacokinetic profile that may further be characterized by a meanAUC_(0h-tlast) of at least 300 ng*ml/h, more preferably of at least 350ng*ml/h. In another specific embodiment, the mean t_(max) may range fromabout 2.2 hrs to about 6 hrs. In another embodiment, the C_(max) mayrange from about 15 ng/ml to about 30 ng/ml.

In another specific embodiment, the active drug may be an activecontraceptive drug. In another specific embodiment, the activecontraceptive drug may be a POC. In another specific embodiment, the POCmay be selected from one or more of the group consisting ofdrospirenone, 17-hydroxy progesterone esters, 19-nor-17-hydroxyprogesterone esters, 17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-I9-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione and dienogest. In onespecific embodiment, the POC may be drospirenone.

The pharmaceutical composition of the invention is particularlyappropriate to be used as a contraceptive, in particular, as a POC. Thepharmaceutical compositions of the invention may also be used forpreparing any other medicaments for which the improvement of the DRSPtolerance may be sought. Such medicaments include, without beinglimiting to, HRT medicament.

Without wishing to be bound by any theory, the present invention showsthat the in vitro dissolution rate of drospirenone is correlated to itspharmacokinetic profile in vivo. A composition displaying apharmacokinetic profile for drospirenone as fully-described above mayexhibit a slow in vitro dissolution rate of drospirenone such that nomore than 50% of drospirenone initially present in the said compositionis dissolved within 30 minutes.

In one aspect, the present invention provides pharmaceuticalcompositions comprising drospirenone that is characterized by a slowdissolution rate of drospirenone in vitro. As used herein, by “a slowdissolution rate of drospirenone in vitro” is meant that the release ofdrospirenone is such that no more than about50% of drospirenoneinitially present in the said composition is dissolved within 30 minuteswhen the said composition is subjected to a dissolution test.

As intended herein, no more than about 50% of the drospirenoneencompasses no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% of thedrospirenone initially present in the contraceptive composition. In someembodiments, no more than about 40% of the drospirenone initiallypresent in the composition is dissolved within 30 min.

As used herein, the percentage of drospirenone is related to the amountof drospirenone initially present in the said contraceptive composition.

The in vitro dissolution rate of any active drug of the presentinvention, including drospirenone, may be assessed by anyone ofwell-known methods described in the prior art. The in vitro dissolutionrate of drospirenone is preferably assessed by the USP XXIII PaddleMethod. Briefly, a tablet consisting of the contraceptive compositioncomprising drospirenone to be tested is placed in 900 mL of water at 37°C. (±0.5° C.). The dissolution test is performed using a USP dissolutiontest apparatus 2 at a stirring rate of 50 rpm.

In the context of the present invention, the term “active drug” includesany compound intended to furnish pharmacological activity or otherdirect effect in the diagnosis, cure, mitigation, treatment and/orprevention of a condition. See 21 C.F.R. 210.3(b)(7). Further, “activedrugs” include those compounds of the composition that may undergochemical change during the manufacture of the composition and be presentin the final composition in a modified form intended to furnish anactivity or effect. Id. As used herein, an “active contraceptive drug”thus means an active drug that may prevent pregnancy when administeredin an effective amount to a female patient through its contraceptiveeffect. The active contraceptive drug may prevent pregnancy to occur byvarious contraceptive effects. For example, the contraceptive effect mayinclude, but is not limited to, one or more of the inhibition ofovulation, thickening of cervical mucus (which reduces the spermviability and penetration) and/ or preventing or otherwise impedingembryo implantation.

The term “drospirenone” includes drospirenone itself, i.e. the chemicalentity identified by the CAS registry Number 67392-87-4, solvates ofdrospirenone, and derivatives or prodrugs of drospirenone.

Drospirenone may be prepared by well-known methods described in theprior art, for example, described in U.S. Pat. No. 4,129,564, WO9806738,EP11746101 or WO2006061309. The method described in WO2006061309 may beparticularly suitable for preparing drospirenone. It goes without sayingthat the method for preparing drospirenone may be performed so as tomeet the Good Manufacturing Practice (GMP) requirements.

To ensure a good bioavailability of the active drug, a significantamount of the active drug initially comprised in the contraceptivecomposition has to be released in a reasonable time range. An in vitrodissolution rate of said active drug may be such that at least 50% ofthe active drug initially present in the said compositions was dissolvedin a time range from about3 hours to about 4 hours. In a specificembodiment, the active drug may be a POC. In another embodiment, the POCmay be drospirenone. Indeed, the Applicant showed that a goodbioavailability of drospirenone was achieved in the case of compositionscomprising drospirenone which had an in vitro dissolution rate ofdrospirenone such that at least about 50% of the drospirenone initiallypresent in the said compositions was dissolved in a time range fromabout 3 hours to about 4 hours.

Accordingly, an object of the present invention is a contraceptivecomposition comprising drospirenone wherein the in vitro dissolutionrate of the said drospirenone is such that no more than about 50% of thesaid drospirenone is dissolved within 30 minutes and such that at leastabout 50% of the drospirenone is dissolved in a time range from 3 hoursto 4 hours.

A time range from about 3 hours to about 4 hours may include, inspecific non-limiting embodiments, a time range from 3.25 hours, to 3.5hours, and from 3.75 hours, to 4 hours.

At least about 50% of the active drug such as drospirenone encompassesat least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, at least 88%, at least90%, at least 91%, at least 92%, at least 93%, at least 94%, at least95%, at least 96%, at least 97%, at least 98%, at least 99%, and atleast 99.5%.

In some embodiments, at least about 60% of the active drug, such asDRSP, initially present is dissolved in a time range from about 3 hoursto about 4 hours. In some other embodiments, the said contraceptivecomposition is further characterized in that at least about 70% of theactive drug, such as drospirenone is dissolved within about 6 hours.

The applicant has shown that specific surface area of DRSP has a directimpact on the in vitro dissolution rate of drospirenone and its in vivopharmacokinetic profile.

One way to obtain the active drug-containing compositions of theinvention is to use the active drug in a particle form having anappropriate specific surface area. Active drugs may be present in thepharmaceutical compositions of the invention in a non-micronizedparticle form. In a specific embodiment, the active drug may be a POC.For example, it has been also shown that the active drug drospirenone ina particle form having a specific surface area from about 2000 cm²/g toabout 8500 cm²/g may be suitable for obtaining the contraceptivecompositions of the invention. The specific surface area may beexperimentally determined using the BET method (gas adsorption method).

In some embodiments, the contraceptive compositions of the inventioncomprises active drugs such as drospirenone in a particle form having aspecific area from about 2000 cm²/g to about 8500 cm²/g. Such a specificarea range which includes values of about 2000 cm²/g, 2500 cm²/g, 3000cm²/g, 3500 cm²/g, 4000 cm²/g, 4500 cm²/g, 5000 cm²/g, 5500 cm²/g, 6000cm²/g, 6100 cm²/g, 6200 cm²/g, 6300 cm²/g, 6400 cm²/g, 6500 cm²/g, 6600cm²/g, 6700 cm²/g, 6800 cm²/g, 6900 cm²/g, 7000 cm²/g, 7500 cm²/g, 8000cm²/g and 8500 cm²/g.

In a specific embodiment, concerning the size particle distribution,active drugs particles having a diameter greater than 200 μm arepreferably avoided. In a specific embodiment, drospirenone particleshaving a diameter greater than 200 μm are preferably avoided in order tonot drastically impair the in vitro dissolution rate and, thus, the invivo bioavailability since such particles are poorly soluble. In aspecific embodiment, drospirenone may preferably have a d50 of less thanabout 70 μm. In a preferred embodiment, the d50 of the drospirenoneparticles may range from about 10 μm to about 60 μm. A d50 ranges fromabout 10 μm to about about 60 μm encompasses a d50 of about 10 μm, ofabout 15 μm, of about 20 μm, of about 25 μm, of about 30 μm, of about 35μm, of about 40 μm, of about 45 μm, of about 50 μm, of about 55 μm andof about 60 μm.

In some embodiments, the particle size distribution of the active drugpresent in the composition according to the invention may becharacterized by:

-   -   (i) a d90 particle size less than about 100 μm, and/or    -   (ii) a d50 particle size ranging from about 10 μm to about 60 μm        and/or    -   (iii) a d10 particle size more than about 3 μm.

In some other embodiments, the d50 of the active drug particles mayrange from about 10 μm to about 30 μm. In a specific embodiment, theactive drug may be a POC. In such embodiments, the particle sizedistribution of the POC present in the composition according to theinvention is characterized by at least one of the followingcharacteristics:

-   -   (i) a d90 particle size less than about 100 μm,    -   (ii) a d50 particle size ranging from about 10 μm to about 30 μm        and    -   (iii) a d10 particle size more than about 3 μm.

In a specific embodiment, the particle size distribution of,drospirenone present in the composition according to the invention maybe characterized by:

-   -   (iv) a d90 particle size less than about 100 μm, and/or    -   (v) a d50 particle size ranging from about 10 μm to about 60 μm        and/or    -   (vi) a d10 particle size more than about 3 μm.

In other specific embodiments, the d50 of drospirenone particles mayrange from about 10 μm to about 30 μm. In such embodiments, the particlesize distribution of the drospirenone present in the compositionaccording to the invention is characterized by at least one of thefollowing characteristics:

-   -   (iv) a d90 particle size less than about 100 μm,    -   (v) a d50 particle size ranging from about 10 μm to about 30 μm        and    -   (vi) a d10 particle size more than about 3 μm.

As used herein, the term “about” before a “specific value” defines arange from “the specific value minus 10% of the specific value” to “thespecific value plus 10% of the specific value”. For example, “about 50”defines a range from 45 to 55. In addition, it may define a range where“the specific value minus at least 20% of the specific value” to “thespecific value plus at least 20% of the specific value.” Further, it maydefine a range where “the specific value minus at least 30% of thespecific value” to “the specific value plus at least 30% of the specificvalue” and so on.

As used herein, by “d90 particle size” is meant that the particle sizedistribution is such that at least 90% of the particles have a particlesize diameter of less than the specified value.

As used herein, by “d50 particle size” is meant that the particle sizedistribution is such that at least 50% of the particles have a particlesize diameter of less than the specified value.

As used herein, by “d10 particle size” is meant that the particle sizedistribution is such that at least 10% of the particles have a particlesize diameter of less than the specified value.

d90 particle size less than about 100 μm may include d90 particle sizesless than about 90 μm, 80 μm, 70 μm, 60 μm, 55 μm, 50 μm, 45 μm, 40 μm,38 μm, 36 μm, 34 μm, 32 μm, 30 μm, 28 μm, 26 μm, 24 μm, 22 μm, and 20μm.

d50 particle size values ranging from about 10 μm to about 30 μm mayinclude values of about 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm,18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28μm, 29 μm, and 30 μm.

d10 particle size values more than about 3 μm may include d10 particlesize values more than about 3 μm, 3.5 μm 4.5 μm, 5 μm, 6 μm, 7 μm, 8 μm,9 μm, 10 μm, 11 μm, and 12 μm. It goes without saying that d10 particlesize value is smaller than d50 particle size value which is smaller thand90 particle value.

The active drug (such as drospirenone) particle size distribution, inparticular d90, d10 and d50 values, may be determined by well-knownmethods of the prior art such as sieve analysis, laser diffractionmethods, photoanalysis or optical counting methods. Laser diffractionmethods are particularly preferred. As illustrated in the Example 1, theparticle size distribution may be determined by laser diffraction in wetdispersion. The dispersant is preferably water.

In some embodiments, the pharmaceutical composition of the invention maycomprise drospirenone in a particle form having a particle sizedistribution having a combination of two characteristics selected from:

-   -   (i) a d90 particle size less than about 100 μm,    -   (ii) a d50 particle size ranging from about 10 μm to about 30 μm        and    -   (iii) a d10 particle size more than about 3 μm.

In other words, the particle size distribution of DRSP display acombination of characteristics selected from characteristic (i) andcharacteristic (ii), characteristic (i) and characteristic (iii), and,characteristic (ii) and characteristic (iii).

In some other embodiments, the pharmaceutical composition of theinvention comprising drospirenone in a non-micronized form having aparticle size distribution characterized in that:

-   -   (i) d90 particle size is less than about 100 μm,    -   (ii) d50 particle size ranging from about 10 μm to about 30 μm        and    -   (iii) d10 particle size is more than about 3 μm

In a preferred embodiment, the DRSP particle distribution may be furthercharacterized in that the d90 particle size value is less than about 50μm and in that no particle has a size greater than about 80 μm.

In some embodiments, the contraceptive composition of the invention maycomprise drospirenone in a particle form having a d90 particle sizewhich ranges from about 20 μm to about 40 μm, a d50 particle size whichranges from about 10 μm to about 30 μm and a d10 which ranges from about3 μm to about 9 μm and wherein no particle has a size greater than about80 μm, more preferably no particle has a size greater than about 60 μm.

In some other embodiments, the contraceptive composition of theinvention may comprise drospirenone in a particle form having:

-   -   (i) a d90 particle size which ranges from about 30 μm to about        40 μm,    -   (ii) a d50 particle size which ranges from about 15 μm to about        25 μm and    -   (iii) a dl0 which ranges from about 5 μm to about 9 μm and        wherein no particle has a size greater than 80 μm, more        preferably no particle has a size greater than 60 μm.

For illustrative purposes, an appropriate particle size distribution ofdrospirenone according to the invention is shown in FIG. 1.

In some other embodiments, the contraceptive composition of theinvention may comprise drospirenone in a particle form having a specificsurface area from about 2000 cm²/g to about 8000 cm²/g and having a d50particle size ranges from about 10 μm to about 60 μm.

To obtain drospirenone in a particle form having the specific surfacearea and/or the particle size distribution as described above, oneskilled in the art may use well-known methods of the prior art such as amilling process optionally combined with a sieve process. For example,drospirenone, obtained by anyone of the synthesis methods described inthe prior art, may be subjected to a ball mill or hammer mill step,optionally followed by vibrating sieve steps. The subsequent vibratingsieve steps may remove the finest and biggest particles of drospirenonewhich would impair the pharmacokinetic profile and the in vitrodissolution profile of drospirenone.

One skilled in the art may adjust the parameters of the milling andsieve steps by routine experiments to obtain the appropriate particleform of drospirenone. Appropriate mills which may be used include afluid energy mill, a ball mill or rod mill, a hammer mill, a cuttingmill and an oscillating granulator.

An appropriate particle form of, a POC, such as drospirenone may also beprepared by a crystallisation or precipitation process optionallycombined with a sieve step in order to fully control the size ofPOC/drospirenone particles. For example, the precipitation process maycomprise the steps of (i) dissolving drospirenone in a water-misciblesolvent and then (ii) dispersing the resulting solution in cold waterunder stirring so that to induce the precipitation of drospirenone. Thedrospirenone particles may be then recovered by a filtration process.

The water-miscible solvents may be a solvent commonly used incrystallisation or precipitation process such as methanol, ethanol,isopropanol, dimethylformamide, tetrahydrofuran, dioxane or dimethylsulfoxide, di methylacetamide or acetone.

Such a process enables one skilled in the art to obtain a POC, such asdrospirenone, essentially in a crystallized form.

By routine experiments, one skilled in the art may determine theparameters of the precipitation process to be used so as to obtain theappropriate form of drospirenone. One skilled in the art may adjust theparameters of the said precipitation process (such as the amounts ofsolvent, of water and optionally that of surfactant to be used) byroutine experiments.

As described above, when the pharmaceutical composition of the inventionis a contraceptive composition, the said composition may provide apharmacokinetic profile of drospirenone such that the presence of anestrogenic compound to ensure the contraceptive efficiency of the saidcompositions is not required.

Accordingly, in specific embodiments, the contraceptive compositions ofthe invention do not comprise an estrogen, including phytoestrogen. Asused herein, the term “estrogen” refers to compounds, such asethinylestradiol, mestranol or the phytoestrogen 8-prenylnaringenin,that are able to bind and activate estrogen receptors. In other words,the DRSP is present in the contraceptive compositions of the presentinvention without estrogen, which means that DRSP is not associated withor combined with an estrogen as in the case of combined oral pill.

In some embodiments, drospirenone is the sole contraceptive ingredientcomprised in the contraceptive compositions, i.e. the sole activeingredient able to prevent pregnancy when administered to a femalepatient of child-age bearing.

However, in some specific embodiments of the present invention,drospirenone may be combined with one or more progestogens. The term“progestogen”, as used herein, refers to any compound that binds andactivates the progesterone receptor.

Progestogens include, but are not limited to, 17-hydroxy progesteroneesters, 19-nor-17-hydroxy progesterone esters, 17 -ethinyltestosteroneand derivatives thereof, 17-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, norgestrel, d-17-acetoxy-13-ethyl-17-a-ethinyl-gon-4-en-3-one oxime, cyproteroneacetate, gestodene, desogestrel, etonorgestrel, norgestimate,norelgestromin, chlormadione and dienogest.

In some other embodiments, the drospirenone may be combined with one ormore active ingredients which do not have contraceptive activities. Suchactive ingredients include, without being limited to, antiemetic agents,vitamins such as folic acid, vitamin B12, vitamin D, minerals and oligoelements such as iron, iodine, selenium and others.

The contraceptive compositions of the invention may comprisedrospirenone in an amount corresponding to a daily dosage which preventspregnancy when the said contraceptive composition is administered to awoman over a single treatment period of 21 to 28 days.

As described in the Example 3 related to a clinical trial, the oraladministration of a single daily dosage unit of a composition accordingto the invention and comprising 3 mg of DRSP, obtains a meanAUC_(0h-tlast) value of 368 ng*h/ml, which corresponds to 88% of themean AUC_(0h-tlast) resulting from the oral administration of a singledose of Yasminelle®.

In a specific embodiment, the pharmaceutical compositions of theinvention may be a contraceptive composition which comprisesdrospirenone in an amount corresponding to a daily dose of at leastabout 2 mg of drospirenone. At least about 2 mg of drospirenone mayencompass at least about 3 mg of drospirenone, at least about 3.5 mg ofdrospirenone, and at least about 4 mg of drospirenone.

In some embodiments, the active daily dosage unit which includes thecontraceptive composition as described above may comprise an active drugin amount ranging from about 2 mg to about 6 mg. In a specificembodiment, the POC may be in an amount ranging from about 2 mg to about6 mg. In another specific embodiment, the POC may be DRSP. A daily doseranging from about 2 mg to about 6 mg may encompass daily doses of 2.0mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, and 6 mg. Ina specific embodiment, the daily dose of the POC, such as DRSP, may beabout 2 mg.

In a specific embodiment, the contraceptive compositions of theinvention may comprise DRSP in an amount corresponding to a daily dosagewhich ensures ovulation inhibition when the said contraceptivecomposition is administered to a woman over a single treatment period of21 to 28 days.

The daily dose of drospirenone may range from about 3 mg to about 6 mg,and specifically from about 3 mg to about 4.5 mg. In some embodiments,the amount of drospirenone may correspond to a daily dose of about 4.0mg. However, the daily dose of drospirenone to be administered to afemale patient in need thereof may also be adjusted depending onindividual factors such as the age, the body weight, the general healthand the diet of the female patient. The said daily dose may also varyupon the drug interaction which may occur. The said daily dose may alsovary upon the additional biological effect(s), other than the preventionof pregnancy, which may be sought through the administration of DRSP.

The daily dose of drospirenone to be daily administered to a femalepatient may be lower or higher than the doses previously mentioned. Forexample, a female patient in peri-menopause may require a higher orlower daily dosage of drospirenone, in order to improve her generalconditions and, for example, in order to improve the regularity of hermenstrual cycles. The adjustment of the daily dosage may be routinelydetermined by practitioners.

In another embodiment of the present invention, the pharmaceuticalcomposition may comprise an active contraceptive drug that allows for a24/4 regimen. As defined herein, a “24/4 regimen” is a daily dosingregimen for establishing its contraceptive effect within a period of atotal of 28 days that allows for the patient to have an activecontraceptive drug administered once a day on 24 days of the 28 period,but allow the patient to skip up to 4 doses of the 28 day daily dosingregimen period. In other words a patient may miss up to 4 doses i.e., 4days of a 28 day period, without taking the active contraceptive drug,and still continue to prevent pregnancy. A non-limiting example of the24/4 regimen is depicted in FIGS. 6a -b. As demonstrated, the subjectswere administered an active contraceptive drug (DRSP) on days 1-24 and aplacebo on days 25-28 of each treatment cycle at a fixed hour. FIGS. 6aand 6b show the 24/4 regimen for two consecutive 28 day periods: thedata show the plotted individual values for plasma progesterone levelsand plasma estradiol levels, respectively. Accordingly, in a specificembodiment of present invention, the prevention of pregnancy may be dueto the inhibition of ovulation.

The results show that during the 2 consecutive 24/4 regimens, noovulation occurred. Conversely, upon cessation of treatment, during the28-day follow-up cycle, the progesterone levels increased above 5.04ng/mL in 17 out of 20 women showing a return of ovulation. The dataconfirms that the composition of the invention, when used as a activecontraceptive drug (DRSP) upon a 24/4 regimen, provided reliableinhibition of ovulation, even due to the patient missing 4 doses duringeach 28 day period. Accordingly. in a specific embodiment, the presentinvention may include a pharmaceutical composition comprising an activecontraceptive drug , wherein the pharmaceutical composition allows for a28 day daily dosing regimen, and wherein after initial administration ofthe active contraceptive drug has established its contraceptive effectin a patient, the patient may skip up to 4 doses within any 28 day dailydosing regimen period.

In another specific embodiment, the active contraceptive drug may be aprogestogen-only contraceptive (POC). In another specific embodiment,the POC may be DRSP. In another specific embodiment, the activecontraceptive drug may inhibit ovulation. In another specificembodiment, the contraceptive effect may comprise inhibiting ovulation.In a specific embodiment of the present invention, a pharmaceuticalcomposition may comprise a progestogen-only contraceptive (POC) forinhibiting ovulation, wherein the pharmaceutical composition allows fora 28 day daily dosing regimen, and wherein after initial administrationof the POC has inhibited ovulation in a patient, the patient may skip upto 4 doses within any 28 day daily dosing regimen period. In a specificembodiment, the POC may be DRSP.

In a specific embodiment, the skipped up to 4 doses may be onnon-consecutive days. In another example, only 2 doses of the 4 skippeddoses may be on non-consecutive days (i.e. 2 skipped doses are onconsecutive days). In another example, only 1 dose of the 4 skippeddoses may be on non-consecutive days (i.e. 3 skipped doses are onconsecutive days). In another embodiment, the skipped 4 doses may be onconsecutive days, and so on.

In another embodiment, the pharmaceutical compositions may comprise aactive contraceptive drug that also allows for a 28 day dosing regimenwherein a patient may skip up to two non-consecutive days of the activecontraceptive drug, provided the skipped dose is taken within about 24hrs afterwards. In other words, the prevention of pregnancy may bemaintained even if the administration of the active contraceptive drugwas delayed for 24 hours in two separate non-consecutive days within the28 day daily dosing regimen. Accordingly, the day after eachnon-consecutive skipped dose, two doses are administered to the patientwithin 24 hrs. FIGS. 6a-b also provides a non-limiting example of thisconcept. During the second 28 day period, the subjects took one tabletof 4 mg DRSP from day 1 to day 24 with the exception of day 5 and day 13of the second 28 day period. On these two days, the tablet intake wasdelayed for 24 hours (i.e., no pill was taken on day 5 and day 13 and atablet was taken once on day 6 and once on day 14, respectively). Thedata demonstrates that ovulation inhibition was maintained even if theadministration of the tablet was delayed for 24 hours in two separatetimes within one 28 day period. Thus, in a specific embodiment, thepresent invention may be a pharmaceutical composition that allows duringa 28 day daily dosing regimen for the patient to skip up to twonon-consecutive days of a active contraceptive drug, provided the activecontraceptive drug skipped dose is taken within about 24 hrs after theup to two skipped non-consecutive days. In another specific embodiment,the up to two skipped non-consecutive days may be included in a 28 daydaily dosing regimen that also includes the 24/4 regimen, i.e., one 28day daily dosing regiment may include 4 days of skipped doses and up totwo non-consecutive days where the dose is delayed. In anotherembodiment, the active contraceptive drug may be a POC. In a specificembodiment, the POC may be selected from one or more of the groupconsisting of drospirenone, 17-hydroxy progesterone esters,19-nor-17-hydroxy progesterone esters, 17α-ethinyl testosterone andderivatives thereof, 17α-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, norgestrel,d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime, cyproteroneacetate, gestodene, desogestrel, etonorgestrel, norgestimate,norelgestromin, chlormadione and dienogest. In a specific embodiment thePOC may be drospirenone. In another specific embodiment, the daily doseof drospirenone may comprise a dosage amount of at least about 2 mg.

The pharmaceutical compositions of the invention are suitable forpatients who are women of child-bearing age. It should be noted that thecontraceptive methods of the invention may be suitable for women whosehealth conditions are not compatible with high peak of drospirenoneplasma concentration. Such women include, without being limited to,subjects with renal impairment, women predisposed to hyperkalemia andsubjects who concomitantly take potassium sparing drugs. Thecontraceptive methods of the invention are also particularly suitablefor women for whom the administration of estrogens is not recommended.Such women include, without being limited to, women predisposed tocardiovascular disorders, women who smoke and breast-feeding women. In aspecific embodiment, the patient may have a higher risk for developing acomplication from the administration of an estrogen than the generalpopulation. In a specific embodiment, the complication from theadministration of an estrogen may be due to the patient having one ormore conditions or characteristics selected from the group consisting ofa higher risk for developing thromboembolism than the generalpopulation, acquired or genetic thrombophilia or hypercoagulability, anage of 35 years or over who smoke cigarettes, a higher risk for strokethan the general population, sickle-cell disease or sickle-cell anemia,a higher risk than the general population for myocardial infarction, andwomen currently lactating.

In a specific embodiment, the pharmaceutical compositions of theinvention may further comprise one or more pharmaceutically acceptableexcipients.

The pharmaceutical compositions of the invention may be formulatedaccording to standard methods such as those described, e.g., inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Lippincott Williams &Wilkins; Twenty first Edition, 2005).

Pharmaceutically acceptable excipients that may be used to formulate thecontraceptive composition of the invention are, in particular, describedin the HANDBOOK OF PHARMACEUTICALS EXCIPIENTS, AMERICAN PHARMACEUTICALASSOCIATION (Pharmaceutical Press; 6th Revised edition, 2009). Examplesof appropriate excipients include, but are not limited to, fillers,carriers, diluents, binders, anti-caking agents, plasticizers,disintegrants, lubricants, flavors, buffering agents, stabilizers,colorants, dyes, anti-oxidants, anti-adherents, softeners, preservativesand glidants.

In some embodiments, the contraceptive compositions of the invention maycomprise one or more excipients selected from the group of binders,fillers, glidants and lubricants. Examples of fillers include, withoutbeing limited to, lactose anhydrous, microcrystalline cellulose, starch,pregelatinized starch, modified starch, dibasic calcium phosphatedihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate,calcium carbonate, lactose, dextrose, sucrose, mannitol and sorbitol andcombinations thereof. Examples of lubricants include, without beinglimited to, magnesium stearate, calcium stearate, zinc stearate, talc,propylene glycol, PEG, stearic acid, vegetable oil, sodium benzoate,sodium lauryl sulfate, magnesium lauryl sulfate, mineral oilpolyoxyethylene monostearate and combinations thereof. Examples ofbinders include, without being limited to, starches, e.g., potatostarch, wheat starch, corn starch; gums, such as gum tragacanth, acaciagum and gelatin; microcrystalline cellulose, hydroxypropyl cellulose,hydroxyethyl cellulose and hydroxypropylmethyl cellulose; polyvinylpyrrolidone and combinations thereof. Examples of glidants includesilicon dioxide, magnesium trisilicate, powdered cellulose, starch, talcand tribasic calcium phosphate.

In a specific embodiment, the pharmaceutical compositions according tothe invention do not comprise a significant amount of a surfactantagent. For example, a significant amount of a surfactant agent mayimpair the in vitro dissolution profile of DRSP by increasing itsinitial rate of dissolution. Surfactant agents include non-ionicsurfactants such as polyoxyethylene sorbitan fatty acid esters and ionicsurfactants such as sodium lauryl sulphate.

In some embodiments, the pharmaceutical composition of the invention maycomprise drospirenone, at least one binder and at least one fillerwherein:

-   -   (i) the amount of drospirenone accounts for 1% to 10% by weight    -   (ii) the amount of the at least one binder accounts for 50% to        65% by weight and    -   (iii) the amount of the at least one filler accounts for 25% to        35% by weight, the percentages by weight being related to the        total weight of the said contraceptive composition.

In some embodiments, the contraceptive composition may further comprisesat least one glidant and at least one lubricant wherein:

-   -   (iv) the amount of the at least one glidant accounts for 0.2% to        6% by weight and    -   (v) the amount of the at least one lubricant accounts for 0.2%        to 0.6% by weight, the percentages by weight being related to        the total weight of the said contraceptive composition.

It goes without saying that the active drug, such as drospirenone, maybe used in a particle form having the specific surface area and/or thed90, d10 and d50 particle sizes which are fully-described in the presentspecification. The said contraceptive composition may optionallycomprise additional excipients which may accounts for about 0.1% toabout 10% by weight.

In some other embodiments, the contraceptive compositions of theinvention comprises drospirenone, at least one binder, at least onefiller, at least one glidant, and at least on lubricant wherein:

-   -   (i) the at least one binder is microcrystalline cellulose    -   (ii) the at least one filler is anhydrous lactose    -   (iii) the at least one glidant is silicon dioxide and    -   (iv) the at least one lubricant is magnesium stearate.

The contraceptive compositions according to the invention may beformulated in a gelanic form suitable for oral administration. Suchforms include, without being limited to, tablets, caplets, granules,pills, capsules, powders and suspension.

In specific embodiments, the contraceptive compositions may beformulated in a solid form for oral administration such as tablets,capsules, granules, caplets and pills. Such solid forms are particularlyappropriate to be used as daily active dosage unit in the contraceptivekit according to the present invention.

When the pharmaceutical composition is formulated in solid forms such astablets or pills, the solid forms may be conveniently coated with asuitable film-forming agent such as hydroxypropylmethyl cellulose,hydroxypropyl cellulose or ethyl cellulose, to which a suitableexcipient may optionally be added, e. g. a softener such as glycerol,propylene glycol, diethylphthalate or glycerol triacetate, a filler suchas sucrose, sorbitol, xylitol, glucose or lactose, or a colorant such astitanium hydroxide, etc. The pharmaceutical composition in the form oftablets, pills or granules may be prepared by conventional methods suchas direct compression, dry granulation and wet granulation. In someembodiments, the solid forms are obtained by direct compression.

A further object of the invention is to provide a method for preparingthe contraceptive composition as described herein which comprises thesteps of:

-   -   (i) providing drospirenone in a particle form as fully-described        previously in the present specification    -   (ii) providing one or more pharmaceutically acceptable        excipients: and    -   (iii) mixing the drospirenone provided in step (i) with the one        or more excipients provided in step (ii).

As fully-described above, the Applicant provides technical guidelines toobtain a composition comprising DRSP in a form such that:

-   -   (i) no more than 50% of the drospirenone initially present in        the said composition is dissolved within 30 minutes and    -   (ii) at least 50% of the said drospirenone is dissolved in a        time range from 3 hours to 4 hours, when the composition is        subjected to an in vitro dissolution test, the percentages of        drospirenone being related to the amount of drospirenone        initially present in the said composition.

A DRSP containing composition with such an in vitro dissolution profileor the in vivo pharmacokinetic profile fully-described above may beachieved by various other ways.

By routine experiments and in view of his general knowledge, one skilledin the art may modify (i) the particle size distribution of DRSP and(ii) the amounts and the nature of excipients in order to obtain otheralternative compositions displaying the in vitro dissolution profile andthe in vivo pharmacokinetic profile described in the presentapplication. For example, one skilled in the art may conceive acomposition comprising (i) micronized DRSP together with (ii) a slowrelease agent in order to diminish the dissolution rate of said DRSP.

One skilled in the art may also combine (i) large particles of DRSPtogether with (ii) a surfactant and/or a wetting agent in order toensure the dissolution of said DRSP. Generally, non-micronized andessentially crystallized form DRSP is preferably used for preparing thepharmaceutical composition of the invention.

2. Contraceptive Methods

In one general embodiment, the present invention provides methods forproducing a particular pharmacokinetic profile of an active drug in apatient. The pharmacokinetic profile may be measured in a patient afterbeing orally administered as a single daily dosage unit of the activedrug to the patient. In another embodiment, the administration of theactive drug to the patient is during fasting conditions. In a specificembodiment, the active drug may inhibit ovulation.

In a specific embodiment, the methods of the present invention mayproduce a particular pharmacokinetic profile based on C_(max), t_(max),and AUC. In a specific embodiment, the methods may comprise producing apharmacokinetic profile of an active contraceptive drug in a patient.

In a specific embodiment, the methods may comprise producing apharmacokinetic profile of an active drug (such as DRSP) in a patient,wherein said pharmacokinetic profile comprises a mean T_(max) rangingfrom about 2.2 hrs to about 6 hrs, and a mean C_(max) which is less thanabout 30 ng/ml, wherein said pharmacokinetic profile is measured in saidpatient after orally administering a single daily dosage unit of saidactive drug to said patient in fasting conditions. In a specificembodiment, the pharmacokinetic profile may additionally comprise anAUC_(0h-tlast) which is at least about 300 ng·h/ml. In another specificembodiment, the AUC_(0h-tlast) is at least about 350 ng·h/ml. In anotherspecific embodiment, the active drug may be an active contraceptivedrug. In another specific embodiment, the active contraceptive drug maybe a POC. In another specific embodiment, the POC may be selected fromone or more of the group consisting of drospirenone, 17-hydroxyprogesterone esters, 19-nor-17-hydroxy progesterone esters,17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione and dienogest. In onespecific embodiment, the POC may be drospirenone.

When orally administered, the pharmaceutical composition of theinvention provides a significantly improved pharmacokinetic profile fordrospirenone characterized by a similar AUC_([0h-tlast]), a delayedt_(max) and a reduced C_(max) as compared to that obtained withYasminelle®. In order to conceive a contraceptive based on the saidpharmaceutical composition, the presence of an estrogen such asethinylestradiol or 8-prenylnaringenin is not required to ensure theovulation inhibition and the cycle stability.

Moreover it is expected that such compositions may be more reliable thanPOCs described in the prior art. The contraceptive compositions of theinvention which do not comprise an estrogen are thus particularlyappropriate to be used as a progestogen-only contraceptive.

Accordingly, another object of the present invention is the use of thepharmaceutical composition as described herein for preparing acontraceptive progestogen-only pill or for preparing a contraceptivekit. A further object of the present invention is to provide an oralcontraceptive method for a female patient in need thereof characterizedin that it comprises the step of administering active daily dosage unitsconsisting of a pharmaceutical composition as fully-described herein tothe female patient over a period of several consecutive days, preferablyover a period of 21 to 28 days.

As used herein a contraceptive method relates to a method for preventingpregnancy. As used herein, “an active daily dosage unit” means a dosageunit which is able to prevent pregnancy when daily administered to afemale patient over a period selected from periods of 21 to 28consecutive days.

In specific embodiments, the active daily dosage unit may inhibitovulation when administered daily to a female patient over a periodselected from periods of 21 to 28 consecutive days

As used herein, a female patient refers to a woman of child-bearing age,i.e. from puberty to menopause. Women of child-bearing age also includewomen in peri-menopause.

In a specific embodiment, the said daily dosage units do not comprise anestrogen. In some embodiments, the drospirenone is the solecontraceptive ingredient comprised in the said contraceptivecomposition.

The contraceptive methods of the invention, in one embodiment, may beperformed for a period of time corresponding to the average length of amenstrual cycle, i.e. 28 days, and may be iterated during severalconsecutive months up to several years or more.

In some embodiments, the contraceptive methods of the invention compriseadministering “continuously” daily dosage units of the invention. Such amethod does not comprise a free-contraceptive period, i.e. a period inwhich no contraceptive is administered.

In other embodiments, the contraceptive method of the inventioncomprises two consecutive phases:

-   -   a first phase wherein active daily dosage units of the invention        which do not comprise estrogen are administered to the female        patient over a period of 21 to 27 consecutive days and    -   a second phase wherein no contraceptive composition is        administered to the female patient over a period of 1 to 7        consecutive days.

As used herein, a period of I to 7 consecutive days include periods of 1day, of 2 consecutive days. of 3 consecutive days, of 4 consecutivedays, of 5 consecutive days, of 6 consecutive days, and of 7 consecutivedays.

As used herein, a period of 21 to 27 consecutive days include periods of21 consecutive days, of 22 consecutive days, of 23 consecutive days, of24 consecutive days, of 25 consecutive days, of 26 consecutive days, andof 27 consecutive days.

As mentioned above, the duration of the first phase plus the secondphase may be 28 days. In the first phase, the composition of activedaily dose units may remain constant, in particular in respect to thedaily amount of drospirenone.

In some other embodiments, the composition of the active daily doseunits may vary, in particular, in respect to the daily amount ofdrospirenone.

The second phase may be a free-contraceptive period, i.e. a phase duringwhich no contraceptive ingredient is administered to the female patient.During the said second phase, daily placebo dosage units may beadministered to the female patient. In some other cases, no pill isadministered to the female patient.

Such a second phase may enable regular menstrual bleedings to occur andthus may enable to mimic the natural menstrual cycle. Moreover, the saidsecond phase enables the secretion of endogenous estradiol, which maybenefit bone metabolism of the female patient.

As used herein, the term “active daily dosage unit” refers to physicallydiscrete units suitable as unitary dosages which include a contraceptivecomposition as fully described hereabove in the present specification.As mentioned previously, the active daily dosage unit may generallycomprise a drospirenone amount of about 3.0 mg to about 6.0 mg, morepreferably, of about 3.5 mg to about 4.5 mg.

In some embodiments, the first phase of the contraceptive method maylast from 21 to 24 consecutive days and the second phase of thecontraceptive method may last from 4 to 7 consecutive days.

In some embodiments, the first phase of the contraceptive method maylast 24 consecutive days and the second phase of the contraceptivemethod may last 4 consecutive days.

The contraceptive methods of the invention may provide a highcontraceptive efficiency without the disadvantages (i.e., spottings,irregular bleedings . . . ) observed for marketed progestogen-onlycontraceptive methods such as Cerazette® (Desogestrel).

The contraceptive methods exhibit a higher reliability than otherprogestogen-only contraceptive methods by allowing the patients to beless compliant with treatment (i.e. allowing episotic missing pills)without risking unwanted pregnancy (see Example 4 hereunder).

The contraceptive methods of the invention are suitable for patients whoare women of child-bearing age. It should be noted that thecontraceptive methods of the invention may be suitable for women whosehealth conditions are not compatible with high peak of drospirenoneplasma concentration. Such women include, without being limited to,subjects with renal impairment, women predisposed to hyperkalemia andsubjects who concomitantly take potassium sparing drugs. Thecontraceptive methods of the invention are also particularly suitablefor women for whom the administration of estrogens is not recommended.Such women include, without being limited to, women predisposed tocardiovascular disorders, women who smoke and breast-feeding women. In aspecific embodiment, the patient may have a higher risk for developing acomplication from the administration of an estrogen than the generalpopulation. In a specific embodiment, the complication from theadministration of an estrogen may be due to the patient having one ormore conditions or characteristics selected from the group consisting ofa higher risk for developing thromboembolism than the generalpopulation, acquired or genetic thrombophilia or hypercoagulability, anage of 35 years or over who smoke cigarettes, a higher risk for strokethan the general population, sickle-cell disease or sickle-cell anemia,a higher risk than the general population for myocardial infarction, andwomen currently lactating.

In another embodiment, the methods of the present invention may compriseadministering a pharmaceutical composition comprising an activecontraceptive drug, wherein the pharmaceutical composition allows for a24/4 regimen. Specifically, the methods may comprise administering acomposition comprising a active contraceptive drug, wherein thepharmaceutical composition allows for a 28 day daily dosing regimen, andwherein after initial administration of the active contraceptive drughas has established its contraceptive effect in a patient, the patientmay skip up to 4 doses within any 28 day daily dosing regimen period. Inanother embodiment, the skipped up to 4 doses may be consecutive ornon-consecutive days. In another embodiment, the methods may include adosing regimen that allows for administration of the tablet to bedelayed for 24 hours in two separate times within one day daily dosingregimen. In a specific embodiment, the methods may include administeringa pharmaceutical composition that further allows during a 28 day dailydosing regimen for the patient to skip up to two non-consecutive days ofa an active contraceptive drug, provided the an active contraceptivedrug skipped dose is taken within about 24 hrs after the up to twoskipped non-consecutive days. In another embodiment, the methods mayallow for the administration of a an active contraceptive drug thatallows for the 24/4 regimen and the up to two delayed non-consecutivedays regimen. In another specific embodiment, the active contraceptivedrug may inhibit ovulation. In another specific embodiment, thecontraceptive effect may comprise inhibiting ovulation.

In another embodiment, the methods of the present invention may compriseadministering a pharmaceutical composition comprising a progestogen-onlycontraceptive (POC) for inhibiting ovulation, wherein the pharmaceuticalcomposition allows for a 24/4 regimen. Specifically, the methods maycomprise administering a composition comprising a POC for inhibitingovulation, wherein the pharmaceutical composition allows for a 28 daydaily dosing regimen, and wherein after initial administration of thePOC has inhibited ovulation in a patient, the patient may skip up to 4doses within any 28 day daily dosing regimen period. In anotherembodiment, the skipped up to 4 doses may be consecutive ornon-consecutive days. In another embodiment, the methods may include adosing regimen that allows for administration of the tablet to bedelayed for 24 hours in two separate times within one day daily dosingregimen. In a specific embodiment, the methods may include administeringa pharmaceutical composition that further allows during a 28 day dailydosing regimen for the patient to skip up to two non-consecutive days ofa POC, provided the POC skipped dose is taken within about 24 hrs afterthe up to two skipped non-consecutive days. In another embodiment, themethods may allow for the administration of a POC that allows for the24/4 regimen and the up to two delayed non-consecutive days regimen. Inanother specific embodiment, the POC may be drospirenone.

The present invention may also comprise methods for sizing drospirenoneto a particular particle size. To obtain drospirenone in a particle formhaving the specific surface area and/or the particle size distributionas described above, one skilled in the art may use well-known methods inthe art such as a milling process optionally combined with a sieveprocess. In a specific embodiment, the methods may comprise sizingdrospirenone to a d50 particle size which may, in a specific embodiment,range from about 10 μm to about 60 μm. In a specific embodiment, themethods may comprise:

-   -   (i) sizing drospirenone to a d50 particle size which ranges from        about 10 μm to about 60 μm by subjecting said drospirenone to        one or mills selected from the group consisting of a ball mill,        a hammer mill, a fluid energy mill, a rod mill, a cutting mill        and an oscillating granulator.

The methods of the present invention may adjust the parameters of themilling and sieve steps by routine experiments to obtain the appropriateparticle form of drospirenone. Appropriate mills which may be usedinclude a fluid energy mill, a ball mill or rod mill, a hammer mill, acutting mill and an oscillating granulator.

An appropriate particle form of a POC, such as drospirenone, may also beprepared by a crystallisation or precipitation process optionallycombined with a sieve step in order to fully control the size ofPOC/drospirenone particles. For example, the precipitation process maycomprise the steps of (i) dissolving drospirenone in a water-misciblesolvent and then (ii) dispersing the resulting solution in cold waterunder stirring so that to induce the precipitation of drospirenone. Thedrospirenone particles may be then recovered by a filtration process.

The water-miscible solvents may be a solvent commonly used incrystallisation or precipitation process such as methanol, ethanol,isopropanol, dimethylformamide, tetrahydrofuran, dioxane or dimethylsulfoxide, dimethylacetamide or acetone.

Such a process enables one skilled in the art to obtain a POC, such asdrospirenone, essentially in a crystallized form.

By routine experiments, one skilled in the art may determine theparameters of the precipitation process to be used so as to obtain theappropriate form of drospirenone. One skilled in the art may adjust theparameters of the said precipitation process (such as the amounts ofsolvent, of water and optionally that of surfactant to be used) byroutine experiments.

3. Contraceptive Kits

The present invention also provides contraceptive kits based on thecontraceptive compositions as fully-described in the presentapplication. Such a kit is particularly suitable for use in thecontraceptive methods as described above.

The said contraceptive kits may comprise one or more packaging units.One or more packaging units may include, without being limited to, 1packaging unit, 2 packaging units, 3 packaging units, 4 packaging units,5 packaging units and 6 packaging units or more.

Each packaging unit may comprise from 21 to 28 daily active dosageunits. As fully described above, each daily active dosage unit mayinclude a contraceptive composition of the invention.

In some embodiments, the contraceptive kit may comprise one or morepackaging units wherein each packaging unit comprises 21 to 28 dailyactive dosage units and wherein each daily active dosage unit comprisesdrospirenone in a non-micronized particle form such that:

-   -   (i) no more than 50% of the drospirenone initially present in        the said daily active dosage unit is dissolved within 30        minutes; and    -   (ii) at least 50% of the said drospirenone is dissolved in a        time range from 3 hours to 4 hours when the daily active dosage        unit is subjected to an in vitro dissolution test, the        percentages of drospirenone being related to the amount of        drospirenone initially present in the said daily active dosage        unit

In one embodiment, the contraceptive kit may comprise one or morepackaging units wherein each packaging unit comprises 21 to 28 dailyactive dosage units and wherein the oral administration of a dailyactive dosage unit provides a pharmacokinetic profile for an active drugcharacterized by one or more of the following features:

-   -   (i) a mean t_(max) of at least about 2.2 h and    -   (ii) a mean C_(max) which is less than about 30 ng/ml.

In some embodiments, the oral administration of the said daily activedosage unit provides a pharmacokinetic profile that may further becharacterized by a mean AUC_(0h-tlast) of at least 300 ng*ml/h, morepreferably of at least 350 ng*ml/h. In another specific embodiment, themean t_(max) may range from about 2.2 hrs to about 6 hrs. In anotherembodiment, the C_(max) may range from about 15 ng/ml to about 30 ng/ml.

In another specific embodiment, the active drug may be an activecontraceptive drug. In another specific embodiment, the activecontraceptive drug may be a POC. In another specific embodiment, the POCmay be selected from one or more of the group consisting ofdrospirenone, 17-hydroxy progesterone esters, 19-nor-17-hydroxyprogesterone esters, 17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime,cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione and dienogest. In onespecific embodiment, the POC may be drospirenone.

In a specific embodiment, the contraceptive kits may comprise one ormore packaging units wherein each packaging unit comprises 21 to 28daily active dosage units and wherein the oral administration of a dailyactive dosage unit provides a pharmacokinetic profile for DRSPcharacterized by one or more of the following features:

-   -   (iii) a mean t_(max) of at least about 2.2 h and    -   (iv) a mean C_(max) which is less than about 30 ng/ml.

In some embodiments, the oral administration of the daily active dosageunit provides a pharmacokinetic profile further characterized by a meanAUC_(0h-tlast) of at least 300 ng*ml/h, more preferably of at least 350ng*ml/h. In another specific embodiment, the mean t_(max) may range fromabout 2.2 hrs to about 6 hrs. In another embodiment, the C_(max) mayrange from about 15 ng/ml to about 30 ng/ml.

As fully described above, in a specific embodiment, the daily activedosage units do not comprise any estrogen or estrogen derivative such asethinyl estradiol, mestranol or 8-prenylnaringenin. In other words, theDRSP may be present in the daily active dosage units without estrogen.

In more embodiments, DRSP is the sole contraceptive ingredient comprisedwithin the daily active dosage units. In some other embodiments, thecontraceptive kit may comprise one or more packaging units wherein eachpackaging unit comprises 21 to 28 daily active dosage units and wherein:

-   -   (a) the amount of the drospirenone in each daily active dosage        unit is at least 2 mg, without estrogen, and    -   (b) the oral administration of a daily active dosage unit        provides a pharmacokinetic profile for DRSP characterized by the        following features:        -   (i) a mean t_(max) ranges from 2.2 h to 6 h and        -   (ii) a mean C_(max) which is less than about 30 ng/ml.

In other embodiments, the contraceptive kit comprises one or morepackaging units wherein each packaging unit comprises 21 to 28 dailyactive dosage units and wherein

(a) the amount of drospirenone in each daily active dosage unit is atleast 2 mg without estrogen; and(b) each daily active dosage unit comprises drospirenone in a form suchthat:

-   -   (i) no more than 50% of the drospirenone initially present in        the said daily active dosage unit is dissolved within 30        minutes; and    -   (ii) at least 50% of the said drospirenone is dissolved in a        time range from 3 hours to 4 hours,    -   when the daily active dosage unit is subjected to an in vitro        dissolution test according to the USP XXIII Paddle Method, the        percentages of drospirenone being related to the amount of        drospirenone initially present in the said daily active dosage        unit.

Each packaging unit may optionally comprise from I to 7 daily dosageunits of a pharmaceutically acceptable placebo. In some embodiments, thecontraceptive kit may be designed so that each packaging unit comprises28 daily dosage units and no daily dosage unit of a pharmaceuticallyacceptable placebo. Such a contraceptive kit is particularly appropriateto perform the contraceptive method of the invention which includesadministering “continuously” DRSP without a free-contraceptive period.

In other embodiments, each packaging unit may comprise:

-   -   21 to 27 active daily dosage units consisting of a contraceptive        composition as fully described in the present application; and    -   optionally, 1 to 7 daily dosage units of a pharmaceutically        acceptable placebo.

Such a contraceptive kit is particularly appropriate to perform thecontraceptive method of the invention which comprises:

-   -   a first phase wherein active daily dosage units of the invention        which do not comprise estrogen are administered to the female        patient over a period of 21 to 27 consecutive days followed by    -   a second phase wherein no contraceptive composition is        administered to the female patient over a period of 1 to 7        consecutive days.

In some other embodiments, each packaging unit of the kit comprises 24daily dosage units comprising an effective amount of a contraceptivecomposition as described herein and, optionally, 4 daily dosage units ofa pharmaceutically acceptable placebo.

In a specific embodiment, the kits of the present invention may compriseone or more packaging units for a 24/4 dosing regimen. In a specificembodiment, the kits may comprise one or more packaging units whereineach packaging unit may comprise up to 28 daily active daily dosageunits comprising comprising an active contraceptive drug in apharmaceutical composition, wherein the pharmaceutical compositionallows for a 28 day daily dosing regimen, and wherein after initialadministration of the active contraceptive drug has established itscontraceptive effect in a patient, the patient may skip up to 4 doseswithin any 28 day daily dosing regimen period. In another embodiment,the skipped up to 4 doses may be on consecutive or non-consecutive days.In another embodiment, the kits may include packaging units thatcomprises a dosing regimen that allows for administration of the tabletto be delayed for 24 hours in two separate times within one 28 day dailydosing regimen period. In a specific embodiment, the kits may allow foradministering a pharmaceutical composition that further allows during a28 day daily dosing regimen for the patient to skip up to twonon-consecutive days of an active contraceptive drug, provided the anactive contraceptive drug skipped dose is taken within about 24 hrsafter the up to two skipped non-consecutive days. In another embodiment,the kits may comprise a composition for administration of an activecontraceptive drug that allows for the 24/4 regimen and the up to twodelayed non-consecutive days regimen. In another specific embodiment,the active contraceptive drug may inhibit ovulation. In another specificembodiment, the contraceptive effect may comprise inhibiting ovulation.

In another specific embodiment, the kits may comprise one or morepackaging units wherein each packaging unit may comprise up to 28 dailyactive daily dosage units comprising a POC for inhibiting ovulation,wherein the pharmaceutical composition allows for a 28 day daily dosingregimen, and wherein after initial administration of the POC hasinhibited ovulation in a patient, the patient may skip up to 4 doseswithin any 28 day daily dosing regimen period. In another embodiment,the skipped up to 4 doses may be on consecutive or non-consecutive days.In another embodiment, the kits may include packaging units thatcomprises a dosing regimen that allows for administration of the tabletto be delayed for 24 hours in two separate times within one 28 day dailydosing regimen period. In a specific embodiment, the kits may allow foradministering a pharmaceutical composition that further allows during a28 day daily dosing regimen for the patient to skip up to twonon-consecutive days of a POC, provided the POC skipped dose is takenwithin about 24 hrs after the up to two skipped non-consecutive days. Inanother embodiment, the kits may comprise a composition foradministration of a POC that allows for the 24/4 regimen and the up totwo delayed non-consecutive days regimen. In another specificembodiment, the POC may be drospirenone.

The packaging units as described above may have one of the conventionalforms usually used for oral contraceptives. For example, the packagingunit may be a conventional blister pack comprising the appropriatenumber of dosage units in a sealed blister pack with a cardboard,paperboard, foil or plastic backing and enclosed in a suitable cover.Each blister container may be conveniently numbered or marked in orderto facilitate compliance.

The packaging unit may contain daily dosage units in the order in whichthey are to be taken, i.e. starting with the first of the at least 21dosage units that contain the combination of drospirenone optionallyfollowed by 7 or less empty blisters, or by 7 or less dosage unitscomprising a pharmaceutically acceptable placebo.

The kit of the invention may comprise other appropriate components suchas instructions for use.

The following examples are illustrative and are not intended to limitthe scope of the invention as claimed.

EXAMPLES Example 1: Preparation of Tablets

a. Preparation of Drospirenone

Drospirenone was prepared according to a process similar to thatdescribed in WO2006/061309. In order to obtain DRSP with an appropriateparticle size distribution, DRSP was subjected to an additional processof precipitation as mentioned in the present application.

Five batches of DRSP were prepared by variants of the above-mentionedprecipitation process.

The analysis of the particle size distribution of each batch wasperformed by laser diffraction method in wet dispersion (Helos sensor,Sympatec with the wet disperser Quixel). The dispersant used was water.The full particle dispersion was ensured by ultrasonication.

The specific area was determined by the BET method. The results obtainedare shown in table 1 below.

TABLE 1 particle size distribution parameters and specific area of DRSPbatches DRSP Batch PR100003 080169 080204 080257 080053 d50 (μm) 22.424.5 13.1 12.6 19.8 d90 (μm) 37.4 37.1 24.8 23.4 34.2 d10 (μm) 5.9 2.94.4 5.3 7.2 d99 (μm) 56.1 48.9 34.5 35.3 44.8 Specific area (m²/g) 0.260.45 0.83 0.77 0.63

The cumulative distribution function and the probability densityfunction for batch 080053 are shown in FIG. 1.

b. Preparation of Tablets According to the Present Invention

The tablets are prepared by direct compression. The composition oftablets is described hereunder.

TABLE 2 composition of tablets (A-3 mg, inventive) Material mg/tablet(%) Drospirenone (Batch 080053) 3.00 4.74 Microcrystalline cellulose 10236.48 57.60 Anhydrous lactose DCL21 20.16 31.83 Silicon dioxide 3.365.31 Magnesium stearate 0.33 0.53 TOTAL 63.33 100.00

Example 2: In Vitro Dissolution Profiles a. Comparison of Tablets A-3 mg(DRSP) with Yasminelle® (Comparative)

The rate of dissolution of drospirenone from the tablets prepared inExample 1 (A-3mg) was determined by the USP XXIII Paddle Method using aUSP Dissolution Test Apparatus 2 including 6 covered glass vessels and 6paddles.

Tablets were placed in 900 ml water at a temperature of 37° C.±(0.5° C.)and stirred at 50 rpm. The amount of drospirenone released in water wasmeasured over several hours. The mean percentages of DRSP released(which were related to the amount of drospirenone initially present inthe each tablet) were calculated and plotted versus time in order toprovide the in vitro dissolution profile of DRSP.

The in vitro dissolution profile of tablets A-3mg (inventive) is shownin FIG. 2 (see curve n° 2).

FIG. 2 also provides the dissolution profile obtained forYasminelle®—tablets which comprised micronized DRSP (comparative) (seecurve n° 4).

Surprisingly, the initial dissolution rate for tablets obtained inExample 1 (A-3 mg) was significantly reduced as compared to that of theYasminelle® tablet since only about 22% of DRSP initially present in thetablets was released within 30 min (versus almost 100% for Yasminelle®in 30 min). The final dissolution percentage of DRSP from tabletsobtained in Example 1 was more than 80%. As described in Example 3, Part1, such an in vitro dissolution profile is correlated with a differentand improved pharmacokinetic profile as compared to Yasminelle®.

b. Examples of Other In Vitro Dissolution Profiles

In order to illustrate the correlation between the in vitro dissolutionprofile of drospirenone and its pharmacokinetic profile upon oraladministration, two other types of DRSP-containing tablets (comparative)were prepared. The composition of these tablets is distinct from that oftablet A-3 mg. Each tablet comprises 3 mg of DRSP in a non-micronizedform.

The first type of tablet (CO1-3 mg) provides a rapid dissolution invitro since about 60% of DRSP initially present in tablets were releasedwithin 30 min according to the USP XXIII Paddle Method (see curve n° 3,FIG. 2).

The second type of tablet (CO2-3mg) displays a very low dissolution rateof DRSP in vitro. No more than of 5% of DRSP initially present intablets were released within 30 min and no more than about 40% of thesaid DRSP was dissolved within 4 hours (see curve n° 1, FIG. 2).

Example 3: Pharmacokinetic Studies Part 1: Evaluation of thePharmacokinetics Parameters for the Composition According to theInvention (Tablet A-3 mg) as Compared to Yasminelle® Objectives

The main objective of the present trial was to assess thebioavailability of an oral test preparation containing drospirenone at3.0 mg (tablets described in Example 1 obtained from batch 080053 (i.e.A-3mg), called hereunder “test product” hereunder) as compared to amarket standard (Yasminelle®, Schering AG, called hereunder “referenceproduct”) after oral administration of a single dose of drospirenone at3.0 mg under fasting conditions in two different periods, 7 days apart.Yasminelle® comprises 3.0 mg DRSP in micronized form and 0.030 mg ofethinylestradiol.

In order to investigate the relative bioavailability of the products,the 90% confidence intervals for the intra-individual ratios (test vs.reference) for the endpoint(s) (AUC0-tlast and Cmax of drospirenone)were determined.

The secondary objective of the present trial was to investigate thesafety of both preparations on the basis of safety clinical andlaboratory examinations (at the beginning and at the end of the trial)and registration of adverse events and/or adverse drug reactions.

Methodology

The study was conducted as a monocentric, open, randomized, single-dose,two-period crossover trial in healthy female volunteers, with durationof hospitalization of approximately 12 h - 13 h after dosing on day 1and with a real wash-out period of 7 days.

Subjects (Planned and Analyzed)

-   -   planned for completion: 10    -   enrolled: 19    -   screened only: 5    -   randomized: 14    -   drop-outs: 0    -   completed as per protocol: 14    -   data set for pharmacokinetic analysis: 14    -   data set for statistical analysis: 14    -   data set for safety analysis: 14

Diagnosis and Main Criteria for Inclusion

[1] female Caucasian

[2] age between 18 and 40 years

[3] physically and mentally healthy as judged by means of a medical,standard laboratory and

gynecological examination

[4] non-smokers since at least 6 months (confirmed by urine cotininetest)

[5] use of an effective non-hormonal method of contraception

List of accepted contraceptive methods

-   -   combination of two barrier methods (female/male condoms,        diaphragms, spermicides)    -   intrauterine device (inert or copper-releasing IUD)    -   existing sterilization (female tubal occlusion)

Duration of Treatment

Each volunteer received in a random way an oral single dose of 1 tabletof the test product or 1 of the reference drug on two single occasions,always under fasting conditions. Both study periods were separated by areal wash-out phase of at least 7 days.

Blood Sampling Points in Each Study Period

Pre-dose, and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00,12:00, 24:00, 48:00 and 72:00 hours post dosing with separation ofplasma. For each endpoint, the quantification of DRSP in plasma wasperformed according to an analytical method adapted from Kirk et al.,(Rapid Communications in mass Spectrometry, 2006, 20:1247-1252).Briefly, Drospirenone was extracted from human EDTA plasma using asolid-phase extraction procedure with HLB 60 mg Oasis cartridges andafterwards derivatized with Girard-P solution, then injected into aliquid chromatograph equipped with a tandem mass spectrometry detector.This method enables the determination of drospirenone in human EDTAplasma over the range 0.25 to 100.40 ng/mL.

Criteria for Evaluation

Pharmacokinetics:

-   -   Primary endpoints: AUC_(0-tlast) and C_(max) of drospirenone    -   Secondary endpoint: t_(max) of drospirenone    -   Additional endpoints: not planned

Safety

Adverse events, clinical and laboratory screening parameters.

Statistical Methods

For pharmacokinetic endpoints:

-   -   parametric method (ANOVA-log) for AUC_(0-tlast) and C_(max) of        drospirenone    -   covariates in the model: sequence, treatment, period, volunteer        within sequence    -   non-parametric method (Hauschke et al. 1990) t_(max) of        drospirenone    -   90% confidence interval for the ratios (test vs. reference) for        AUC_(0h-tlast) and C_(max) of drospirenone

For evaluation of safety:

-   -   descriptive statistical evaluation only.

Bioavailability:

The 90% confidence intervals of log-transformed values were calculatedfor the intra-individual ratio test vs. reference for AUC_(0h-tlast) andC_(max) of drospirenone (and then only interpreted in a descriptive way,and not compared with the usual acceptance ranges for the respectiveparameters (CPMP/EWP/QWP/1401/98, July 2001) as the current trial didnot have the aim of proving bioequivalence). The 90% confidence intervalwas calculated for the intra-individual ratio for the difference oft_(max) (test-reference) and descriptively assessed.

Results

Pharmacokinetics:

A total number of 14 volunteers completed the trial according to theprotocol. The samples of 14 volunteers were analyzed and 14 volunteerswere subjected to statistical evaluation. The endpoints of the analysisof drospirenone after an oral single dose of 1 tablet (drospirenone 3.0mg) of the test preparation or I film-coated tablet (0.03 mg ethinylestradiol and 3 mg drospirenone) of the reference product of the 14volunteers who were subject to pharmacokinetic and statisticalevaluation are summarized in table 3 hereunder.

TABLE 3 Pharmacokinetic endpoints (primary, secondary, and additional)of drospirenone for test product (TEST) and reference product(REFERENCE). Variable geom. mean arithm. mean SD CV Range median TEST (N= 14) AUC0-tlast 360.96 368.55 75.83 20.6 234.72-482.91 359.33 [ng*h/mL]AUC0-inf 452.93 462.00 93.26 20.2 312.60-624.12 463.65 [ng*h/mL] AUCres[%] 19.12 20.04 6.62 33.0 12.13-33.70 17.70 Cmax [ng/mL] 16.46 17.365.50 31.6  6.39-27.79 17.41 tmax — 3.57 1.01 28.3 2.00-5.00 3.50 MRT [h]— 44.08 9.69 22.0 33.64-64.18 40.89 t^(1/2) [h] — 31.87 6.29 19.724.59-44.43 29.42 REFERENCE (N = 14) AUC0-tlast 414.60 418.58 60.46 14.4337.80-527.81 397.70 [ng*h/mL] AUC0-inf 503.65 509.25 77.76 15.3386.08-654.48 510.74 [ng*h/mL] AUCres [%] 17.12 17.58 4.18 23.811.19-27.61 18.47 Cmax [ng/mL] 34.91 35.43 6.32 17.8 24.30-45.96 35.24tmax — 1.57 0.55 35.0 1.00-3.00 1.50 MRT [h] — 38.81 6.45 16.629.68-56.00 39.39 t^(1/2) [h] — 29.78 4.41 14.8 25.21-43.30 28.47

The 90% confidence intervals for the intra-individual ratios(test/reference) for AUC_(0-tlast) and C_(max) of drospirenone, as wellas differences (test-reference) for t_(max) of drospirenone arepresented in table 4 hereunder.

TABLE 4 90% confidence intervals of drospirenone confidence VariablePoint estimator limits*** ANOVA-log (%) AUC0-tlast (ratiotest/reference) 0.8706* 0.8081-0.9380* 11.1% Cmax (ratio test/reference)0.4715* 0.3930-0.5658* 27.6% tmax [h] (difference test-reference)1.7650** 1.5000-2.5000** — *parametric confidence interval**non-parametric confidence interval ***14 volunteers subjected tostatistical evaluation

The concentration-time curves of drospirenone after administration of anoral single dose of I tablet of the test preparation and tablet of thereference product are to be found in FIG. 3a for both preparations(arithmetic means).

The evaluation of bioavailability of the primary endpoints AUC_(0-tlast)and C_(max) of drospirenone was based on a parametric method(ANOVA-log).

The 90%-confidence interval calculated by means of ANOVA-log for thefirst primary endpoint, intra-individual ratio (T/R) of AUC_(0-tlast) ofwas between 0.8081 and 0.9380. The 90%-confidence interval calculated bymeans of ANOVAlog for the second primary endpoint intra-individual ratio(T/R) of C_(max) of drospirenone was between 0.3930 and 0.5658. Thesecondary endpoint t_(max) the 90%-confidence interval for theintra-individual differences was between 1.5000 and 2.5000 hours. Thepoint estimator for the difference of t_(max) of drospirenone was 106minutes (the concentration maxima after administration of the testpreparation being observed later).

It is well known in the art that drospirenone isomerizes into abiologically inactive isomer in acidic conditions, including in theacidic conditions that are encountered in the human stomach.

When conducting the present pharmacokinetics study, assays for detectingthe eventual presence of the inactive isomer of drospirenone in theplasma of the treated women have been performed. The results have shownthat the amount of inactive isomer of drospirenone in the plasma samplescollected from the clinically tested women subjects was below thedetectable level (<1 ng/ml), which means that the pharmaceuticalcomposition that has been used is adapted to release the full amount ofdrospirenone in its biologically active form to the target organs.

Safety

The test formulation and the reference drug were well tolerated.Seventeen non-serious adverse events (AEs) were registered in 11subjects in the course of the trial:

-   -   nine AEs were observed in 8 subjects after administration of        test product.    -   eight AEs were observed in 7 subjects after administration of        reference drug.

All adverse events were assessed as not serious. All adverse events wereassessed as possibly related by the investigator. All AEs resolvedcompletely within relative short frame time. The results of laboratoryscreening gave no indications for adverse events or adverse drugreactions.

CONCLUSIONS

Based on the AUC_(0-tlast) of drospirenone, the extent of absorption ofthe test product is similar to that of the reference product but therate of absorption is significantly delayed resulting in an increasedand decreased The tolerability of test product and the reference productwas similarly good.

Part 2: Evaluation of Other Comparative Tablets CO1-3 mg and CO2-3 mg asCompared to Yasminelle®

The main objective of this second trial was to further illustrate thecorrelation between in vitro dissolution profile and pharmacokineticsparameters for oral tablets comprising DRSP. The oral test tablets weretablet CO1-3 mg and tablet CO2-3 mg which display a rapid in vitrodissolution rate for DRSP and a very slow dissolution rate for DRSP,respectively (see Example 2b).

The reference product was Yasminelle®. The methodology for this secondtrial was similar to that of the trial described in part 1 hereabove.

Briefly, the bioavailability of two oral test preparations (namely CO1-3mg and CO2-3 mg) as compared to that of the market standard(Yasminelle®, Schering AG) was assessed after oral administration of asingle tablet in each case (corresponding to 3 mg of DRSP) under fastingconditions in three different periods, 7 days apart. In order toinvestigate the relative bioavailability of the products, the 90%confidence intervals for the intraindividual ratios (CO1-3 mg vs.reference product and CO2-3 mg vs. reference product) for theendpoint(s) (AUC_(0-tlast) and C_(max) of drospirenone) was determined.

The study was conducted as a monocentric, open, randomized, single-dose,three-period crossover trial in healthy female volunteers, with aduration of hospitalization of approximately 12 h-13 h after dosing.

Each volunteer received randomly an oral single dose of drospirenone 3.0mg (either 1 test tablet CO1-3 mg or 1 test tablet CO2-3 mg or lfilm-coated tablet of Yasminelle®) on three single occasions underfasting conditions.

The three study periods were separated by a real wash-out phase ofbetween 7 days and 10 days.

Subjects (Planned and Analyzed)

-   -   planned for completion: 10    -   enrolled: 18    -   screened only: 4    -   randomized: 14    -   drop-outs: 0    -   completed as per protocol: 14    -   data set for pharmacokinetic analysis: 14    -   data set for statistical analysis: 14    -   data set for safety analysis: 14

Results

The concentration-time curves of drospirenone after administration of anoral single dose of 1 tablet of each product (namely, CO1-3 mg, CO2-3 mgand Yasminelle®) are in FIG. 3b (arithmetic means). As a reminder, CO1-3mg displayed a rapid dissolution rate for DRSP in vitro (about 60%within 30 min). The pharmacokinetic profile obtained for CO1-3 mg isvery close to that of Yasminelle® except for the C_(max). Interestingly,the mean C_(max) of CO1-3 mg was 30 ng/ml versus 36 ng/ml forYasminelle®. The AUC_(0h-tlast) for CO1-3 mg was similar to that ofYasminelle® (410.58 ng*h/ml versus 440.14 ng*h/ml).

On the other hand, CO2-3 mg surprisingly displays a very low dissolutionrate of DRSP in vitro since no more than of 5% of DRSP initially presentin tablets were released within 30 min and no more than about 40% of thesaid DRSP was dissolved within 4 hours. The composition displays areduced and a delayed t_(max) as compared to Yasminelle®. However, themean AUC of said composition was low.

These pharmacokinetics results combined with in vitro results describedin Example 2 illustrate the correlation between the in vitro dissolutionrate of DRSP and its pharmacokinetics profile (in particular for C_(max)and t_(max)), upon oral administration.

Example 4: Simulation Curves Based on Experimental Data Obtained in theClinical Trial Described in Example 3, Part 1

The DRSP mean plasma concentration versus time curves, which is expectedto be obtained from the oral administration of one tablet described intable 2 but containing 4 mg of DRSP from batch 80053 (namely, A-4 mg),was extrapolated from experimental data obtained in the clinical trialdescribed in Example 3 with the assumption that the DRSP plasmaconcentration is proportional to the administered oral amount of DRSP.

The resulting curve for tablet A-4 mg is shown in FIG. 3a and FIG. 4aand compared with that obtained with Yasminelle® and with the tablet A-3mg described in table 2.

As illustrated in FIGS. 4a and 4 b, increasing the DRSP amount from 3 mgto 4 mg in the tablet described in table 2 is expected not to modify thet_(max), which may remain significantly delayed as compared to that ofYasminelle®. The C_(max) is expected to be increased but to remainsignificantly lower than that of Yasminelle® (no more than 60% that ofYasminelle®). Interestingly, the mean plasma concentration is expectedto be higher than that of Yasminelle® after the concentration peak.

FIG. 4c shows the mean DRSP plasma concentration versus time curveswhich are expected to result from the repeated administration every 24hours of one tablet of Yasminelle® (curve n° 1), one tablet of A-3 mg(curve n° 3) and one tablet of A-4mg (curve n° 2).

The curves obtained for the compositions of the invention (namely curvesn° 3 and n° 2) show less difference between mean C_(max) and meanC_(min) (minimal DRSP concentration) than the Yasminelle® composition.The repeated administration of the compositions of the invention thusprovides a more stable DRSP plasma concentration with lower C_(max) thanYasminelle®. Such a fact improves the bleeding profile and reduces theside effects of DRSP when the compositions of the invention are used asa contraceptive.

In the case of tablet A-4 mg, it should be noted that the mean plasmaconcentration is higher than that obtained of Yasminelle® for the timeperiod between t_(max) and the time of the next tablet intake, whichprovides a higher contraceptive reliability. Thus, Tablet A-4 mg isexpected to be appropriate as a progestogen-only pill.

Example 5: Another Example of Composition According to the InventionPart 1: In Vitro Dissolution Profile

Tablets (B-4 mg) were prepared as described in Example 1 from DRSP batchN° PR 100003. Each tablet comprises 4.0 mg of DRSP and excipients in asimilar amount to that described in Table 1. The tablets (B-4 mg) werefurther coated with a suitable film-forming agent, as described in thespecification.

The resulting tablets were subjected to a dissolving in vitro test asdescribed in Example 2. The mean in vitro dissolution profile of saidtablets is shown in FIG. 5 a.

The initial dissolution rate for DRSP was significantly reduced ascompared to Yasminelle® since only about 22% of DRSP initially presentin tablets were released within 30 min. However, about 66% and about 77%of DRSP initially present in tablets were released within 4 h and 6 hrespectively.

The in vitro dissolution profile for tablets B-4 mg was similar to thatof tablet A-3 mg (see example 1). Such a fact illustrates that thespecific area of DRSP does not significantly impair its in vitrodissolution if the said DRSP displays appropriate d50, d90 and d10.

Part 2: Evaluation of the Pharmacokinetics Parameters for theComposition According to the Invention (tablet B-4 mg) as Compared toYasminelle® a. Methodology

The pharmacokinetics parameters for tablet B-4 mg were determined asdescribed in Example 1, part 1.

Briefly, the bioavailability of the test preparation (namely B-4 mg) ascompared to that of the market standard (Yasminelle® , Schering AG) wasassessed after oral administration of a single tablet in each case underfasting conditions in three different periods, 7 days apart.

The DRSP oral dose was 3 mg for Yasminelle® versus 4 mg for tablet B-4mg (inventive). In order to investigate the relative bioavailability ofthe products, the 90% confidence intervals for the intraindividualratios (B-4 mg versus Yasminelle®) for the endpoint(s) (AUC_(0-tlast)and C_(max) of drospirenone) were determined.

The study was conducted as a monocentric, open, randomized, single-dose,three-period crossover trial in healthy female volunteers, with durationof hospitalization of approximately 12 h-13 h after dosing.

Each volunteer randomly received an oral single dose of drospirenone(either one test tablet B-4mg or one tablet of Yasminelle®) on twosingle occasions under fasting conditions. Both study periods wereseparated by a real wash-out phase of between 7 days and 10 days.

Subjects (Planned and Analyzed)

-   -   planned for completion: 10    -   enrolled: 15    -   screened only: 5    -   randomized: 10    -   drop-outs: 0    -   completed as per protocol: 10    -   data set for pharmacokinetic analysis: 10    -   data set for statistical analysis: 10    -   data set for safety analysis: 10

b. Results

Yasminelle® and the test product were well-tolerated by all thepatients.

The concentration-time curves of drospirenone after administration of anoral single dose of I tablet of each product (namely, tablet B-4 mg andYasminelle®) are to be found in FIG. 5b (arithmetic means). The resultsof said trial are further shown in table 5 hereunder.

TABLE 5 Pharmacokinetic endpoints of drospirenone for tablet B-4mg(TEST) and Yasminelle ® (REFERENCE) Variable geom. mean arithm. mean SDCV range median TEST (N = 10) AUC0-tlast 428.07 438.85 104.53 23.8320.74-634.58 419.05 [ng*h/mL] Cmax [ng/mL] 18.96 19.81 6.14 31.012.42-30.17 19.40 tmax [h] — 3.900 0.876 22.5 3.000-5.000 4.000REFERENCE (N = 10) AUC0-tlast 386.68 394.88 90.22 22.8 271.57-615.65391.49 [ng*h/mL] Cmax [ngh/mL] 32.52 32.85 4.85 14.8 23.97-42.80 33.39tmax [h] — 1.700 0.979 54.1 1.000-4.000 1.500

The pharmacokinetics profile for DRSP obtained after the oraladministration of one tablet B-4 mg correlated with the DRSPpharmacokinetics profile expected on the basis of simulations (seeExample 4).

The mean t_(max) for tablet B-4 mg was significantly delayed as comparedto that of Yasminelle® (3.9 h versus 1.7 h). Furthermore, the meanC_(max) obtained for tablet B-4 mg was significantly lower than that ofYasminelle® (19.8 versus 32.9 ng*h/ml). The mean C_(max) for tablet B-4mg corresponded to about 58% of Yasminelle® C_(max) whereas, in Example1, the mean C_(max) for tablet A-3mg corresponded to 49% of that ofYasminelle®; the increase of DRSP dose in tablets did not induce asignificant change in mean C_(max) values.

On the other hand, the increase of DRSP dose significantly improved themean AUC_(0h-tlast) since the mean AUC_(0h-tlast) for tablet B-4 mg was111% of Yasminelle. In Example I, the mean AUC_(0h-tlast) for tablet A-3mg was only 86% of that of Yasminelle®.

In other words, the present results clearly show that compositions ofthe invention allow for a high value of mean AUC_(0h-tlast) combinedwith a low mean C_(max) and a delayed mean t_(max) for DRSP, as comparedto Yasminelle®. The repeated administration of tablets B-4 mg every 24hours will certainly provide a DRSP plasma concentration profile similarto that expected for tablet A-4 mg (see FIG. 4C, curve n° 2).

Accordingly, the compositions of the present invention, such as tabletA-4 mg and tablet B-4 mg, are appropriate to be used ascontraceptive-only pills. Such contraceptives have a good tolerance andto prevent the occurrence of side-effects related to high and fluctuatedDRSP plasma concentrations.

Part 3: Evaluation of the Contraceptive Efficiency of the PharmaceuticalComposition According to the Invention

The aim of the study is to illustrate that a contraceptive pillaccording to the invention which comprises DRSP as the solecontraceptive agent and which is administered upon a 24/4 regimen allowsfor the inhibition of ovulation even in the case of episodic delay ofadministering the pill.

The contraceptive pill is made of 24 tablets B-4 mg as defined inExample 5, Part 2 hereabove and 4 placebo tablets.

a. Methodology

The study was an open-label monocentric trial. Subjects eligible for thestudy were aged 20-30 years, had a body mass index <30 kg/m², regularmenstrual cycles (at least 4 regular cycles in the past 6 months) andwere willing to use condoms during the entire duration of the study.Excluded were subjects with a (suspected) pregnancy, active or pastthromboembolic disorder, present or past severe hepatic disease,carcinoma of the endometrium or other known or suspectedestrogen-dependent neoplasia, undiagnosed vaginal bleeding, use of liverenzyme-inducing drugs and other drugs.

A total of 20 women were enrolled in this trial and performed the twotreatment cycles and the follow-up cycle.

TABLE 6 Parameters of enrolled patients Systolic Diatolic Heart bloodblood rate Weight BMI pressure pressure (beats/ Age (kg) (Kg/m²) (mmHg)(mmHg) mm) Mean ± 24.6 ± 2.4 60.28 ± 7.95 22.76 3.19 110.3 ± 10.3 64.1 ±7.0 65.4 ± 5.7 Std dev Median 24.5 59.1 22.39 115.0 62.5 64.0 Min, Max20; 29 50.0; 79.2 18.1; 30.0 90; 120 50; 80 58; 80

The subjects received daily treatment with tablets containing 4 mg DRSPwith a 24/4 regimen during two cycles. The subjects started treatment onthe 1st day of the cycle (i.e., the first day of onset of vaginalbleeding) following the screening visit. The subjects took one tablet of4 mg DRSP from day 1 to day 24 and one placebo tablet from day 25 to day28 of each treatment cycle at a fixed hour, with the exception of day 5and day 13 of the second cycle. On these two days, the tablet intake wasdelayed for 24 hours (i.e., no pill was taken on day 5 and day 13 and atablet was taken once on day 6 and once on day 14, respectively). Thecomplete study consisted of a 56-day treatment period and a 28-daypost-treatment follow-up period. After informed consent was obtained,the subjects underwent a gynecological examination and a general medicalexamination, including 12-lead ECG, hematology, biochemistry andurinalysis laboratory tests. After compliance with the eligibilitycriteria was confirmed, and after performing a urine pregnancy test witha negative result on the first day of onset of vaginal bleeding, thesubject was included in the study and began taking the study medication.

Blood sampling for hormonal determination (progesterone,17-beta-estradiol, FSH and LH) was performed every 3 days from day 1 today 84 and assessments of weight, blood pressure and heart rate wereperformed at each visit. Serum progesterone, 17-beta-estradiol, FSH andLH concentrations were measured with validated commercial in vitrodiagnostic kits (VIDAS, ELFA Biomerieux). Internal controls wereincluded in each set of samples.

Two urine pregnancy tests were performed during the study:

-   -   at the visit on day 1 of the first cycle in order to verify the        exclusion criterion “pregnant woman” just before starting the        study treatment (the subject was to be excluded if this test was        positive); and    -   at the visit on day 7 of the follow-up cycle.

The occurrence of ovulation during treatment was determined on the basisof serum progesterone concentration, using the criteria of Landgren etal. Thus, an ovulation was judged to have occurred in case ofprogesterone concentrations >5.04 ng/ml-sustained for at least 2consecutive progesterone samples.

b. Results

FIGS. 6a and 6b show the plotted individual values for plasmaprogesterone levels and plasma estradiol levels, respectively. For allwomen, progesterone level values were systematically lower than 5.04ng/ml during the entire treatment period (including placebo period). Themaximum value of progesterone was observed to be 3 ng/mL for a solewoman and for only one time during the treatment periods (includingplacebo period).

These results surprisingly show that during the 2 cycles, no ovulationoccurred. Conversely, upon cessation of treatment, during the 28-dayfollow-up cycle, the progesterone levels increased above 5.04 ng/mL in17 out of 20 women showing a return of ovulation. The minimum time tothe first level of progesterone to be above 5.04 ng/mL was on day 15after the last placebo tablet.

During the 2 cycles under treatment, the mean estradiol levels weresignificantly lower in comparison with those measured during thefollow-up cycle. Noticeably, the secretion of estradiol is not totallyinhibited during the treatment period.

To conclude, the data surprisingly demonstrate that the compositions ofthe invention, when used as a POC upon a 24/4 regimen, provided reliableinhibition of ovulation even in the presence of a placebo period. Thisovulation inhibition was maintained even if the intake of the tablet wasdelayed for 24 hours in two separate times within one cycle.

In view of these experimental data, the compositions of the presentinvention exhibit similar reliability and efficiency as traditionalcombined pill such as Yasmine®, but with less side-effects, for example,on the cardiovascular system.

Example 6: Another Example Composition According to the Invention

Tablets comprising 4 mg of drospirenone (C-4mg) are prepared by directcompression. The composition of tablets is described hereunder.

TABLE 7 Composition of tablets (C-4 mg, inventive) Material mg/tabletDrospirenone (PR 100311) 4.00 Microcrystalline cellulose PH102 33.02Anhydrous lactose PS = 20%, <45 μm 17.50 Silicon dioxide 0.29 Magnesiumstearate 0.33 Coating (Opadry II 85F18422 white) 1.65 TOTAL 56.75DRSP batch PR100311 is characterized by a specific area of 0.66 m²/g.The in vitro dissolution rate and the pharmacokinetic parameters forthese tablets were determined as described in Example 2 and Example 3,respectively.

TABLE 8 In vitro DRSP dissolution rate and DRSP pharmacokinetic profilefor tablets C-4 mg In vitro % of DRSP dissolved 45.8 Dissolution within30 min % of DRSP dissolved 88.3 within 4 h Pharmacokinetics Mean C_(max)(ng/ml) 26 Mean t_(max) (h) 3.6 Mean AUC_(0-tlast) (ng*h/mL) 643

1-168. (canceled)
 169. A method of providing contraception in a patient,the method comprising: administering orally daily under a 28 consecutiveday dosing regimen an active pharmaceutical composition comprising about2 mg to about 6 mg of drospirenone and one or morepharmaceutically-acceptable excipients to said patient; wherein said 28consecutive day dosing regimen comprises: administering said activepharmaceutical composition for 24 consecutive days followed by 4consecutive days wherein no active pharmaceutical composition isadministered to said patient; and administering said activepharmaceutical composition daily at approximately the same time of daysuch that the interval between two dosages is approximately 24 hours;wherein said pharmaceutical composition, when orally administered tosaid patient under fasting conditions, provides a pharmacokineticprofile for drospirenone having: (i) a mean T_(max) ranging from about2.2 hours to about 6 hours; (ii) a mean C_(max) which is less than about30 ng/ml; and (iii) an AUC_(oh-tlast) which is at least 300 ng·h/ml;wherein the dissolution rate of said particle form of said drospirenonein said pharmaceutical composition is such that when subjected to an invitro dissolution test according to the USP XXIII Paddle Method: no morethan 50% of said drospirenone initially present in said pharmaceuticalcomposition is dissolved within 30 minutes, and at least 50% of saiddrospirenone is dissolved in a time range from 3 hours to 4 hours; andwherein said pharmaceutical composition does not contain an estrogen.170. The method of claim 169, further comprising: administering aplacebo dosage unit during said 4 consecutive days wherein no activepharmaceutical composition is administered to said patient.
 171. Themethod of claim 170, further comprising: providing said activepharmaceutical compositions and said placebo dosage units in solid formsselected from the group consisting of: tablets, caplets, granules,pills, capsules, powders, and suspensions.
 172. The method of claim 171,wherein said active pharmaceutical compositions and said placebo dosageunits are both provided in tablet form.
 173. The method of claim 172,wherein said active pharmaceutical composition tablets and said placebodosage unit tablets further comprise a coating comprising a film-formingagent and one or more suitable excipients.
 174. The method of claim 173,wherein said film-forming agent is selected from the group consistingof: hydroxypropylmethyl cellulose, hydroxypropryl cellulose, and ethylcellulose.
 175. The method of claim 173, wherein said one or moresuitable excipients of said coating are selected from the groupconsisting of: softeners, fillers, and colorants.
 176. The method ofclaim 175, wherein said colorants of said one or more suitableexcipients of said coating are white for active pharmaceuticalcomposition tablet coatings and green for said placebo dosage unittablet coatings.
 177. The method of claim 169, wherein said patient maymiss one daily dosage of said active pharmaceutical composition withinsaid 28 consecutive day dosing regimen, the method further comprising:administering said missed dosage of said active pharmaceuticalcomposition as soon as possible, but within about 24 hours; and resumingsaid daily administration for the remaining days within said 28consecutive day dosing regimen.
 178. The method of claim 169, whereinsaid patient may miss 2 or more non-consecutive daily dosages of saidactive pharmaceutical composition within said 28 consecutive day dosingregimen, the method further comprising: administering said misseddosages of said active pharmaceutical composition as soon as possible,but within about 24 hours; and on each occasion, resuming said dailyadministration for the remaining days within said 28 consecutive daydosing regimen.
 179. The method of claim 169, wherein saidpharmaceutical composition is self-administered by said patient. 180.The method of claim 169, wherein said drospirenone is provided inparticle form having a size distribution characterized by: (i) a d₉₀particle size of less than 100 μm; (ii) a d₅₀ particle size in the rangeof about 10 μm to about 60 μm; and (iii) a d₁₀ particle size of morethan 3 μm.
 181. The method of claim 180, wherein said drospirenoneparticles are obtained by a process consisting of: milling,crystallization, precipitation, sieve, or a combination thereof. 182.The method of claim 181, wherein said milling process comprisessubjecting said drospirenone to one or more mills selected from thegroup consisting of: a fluid energy mill, a ball mill, a rod mill, ahammer mill, a cutting mill, and an oscillating granulator.
 183. Themethod of claim 169, wherein said one or morepharmaceutically-acceptable excipients comprises talc, microcrystallinecellulose, anhydrous lactose, silicon dioxide, and magnesium stearate.184. The method of claim 169, wherein said drospirenone is provided inan amount of about 4 mg.
 185. The method of claim 169, wherein saidpharmaceutical composition exhibits improved pharmacokinetics ascompared to combined oral contraceptives containing drospirenone. 186.The method of claim 185, wherein said improved pharmacokineticscomprises one or more of the following: a delayed mean T_(max), areduced mean C_(max), and a reduced mean AUC_(oh-tlast).
 187. The methodof claim 169, wherein said pharmacokinetic profile improves thetolerance of said drospirenone as compared to combined oralcontraceptives containing drospirenone.
 188. The method of claim 187,wherein said improved tolerance comprises a reduction in side-effectscomprising one or more of the following: hyperkalemia, spotting, andirregular bleeding.
 189. The method of claim 169, wherein saidpharmacokinetic profile improves said patient's bleeding profile ascompared to conventional progestogen-only contraceptives.
 190. Themethod of claim 189, wherein said improved bleeding profile comprises areduction in the incidence of unscheduled spotting and bleeding.